Heterocyclic derivatives for the treatment of diabetes and other diseases

ABSTRACT

The present invention relates to certain substituted heterocycles of Formula (I) which are useful in the treatment of diseases related to lipid and carbohydrate metabolism, such as type 2 diabetes, adipocyte differentiation, uncontrolled proliferation, such as lymphoma, Hodgkin&#39;s Disease, leukemia, breast cancer, prostate cancer or cancers in general; and inflammation, such as osteoarthritis, rheumatoid arthritis, Crohn&#39;s Disease or Inflammatory Bowel Disease.

This application claims priority to the U.S. provisional applicationSer. No. 60/151,670, filed Aug. 31, 1999, the disclosure of whichapplication is hereby incorporated in its entirety by this reference.

BACKGROUND OF THE INVENTION

Type 2 diabetes, also referred to as non-insulin dependent diabetesmellitus (NIDDM), afflicts between 80 and 90% of all diabetic patientsin developed countries. In the United States alone, approximately 15million people, and more than 100 million worldwide, are affected.Because this disorder is a late onset disease and occurs often inoverweight persons it can be expected that the number of patientssuffering from this disease will increase further. Patients sufferingfrom type 2 diabetes usually still produce insulin but becomeincreasingly resistant to their own insulin and to insulin therapy. Apromising new class of drugs has been recently introduced thatresensitizes patients to their own insulin (insulin sensitizers),thereby reducing blood glucose and triglyceride levels, and thusabolishing, or at least reducing, the requirement for exogenous insulin.Troglitazone (Resulin™) and rosiglitazone (Avandia™) belong to thethiazolidinediones (TZD) class of chemicals, and are the firstrepresentatives of this class of chemicals approved for the treatment oftype 2 diabetes in the United States and several other countries. Thesecompounds, however, have side effects including rare but severe livertoxicities (i.e., troglitazone) and they can increase body weight inhumans. Such side effects are of major concern for patients who mightrequire treatment for a decade or longer. Therefore, new and betterdrugs for the treatment of type 2 diabetes and related disorders areneeded. New heterocyclic derivatives that are useful, for example, tomodulate metabolism (such as, for example, lipid metabolism andcarbohydrate metabolism) or adipocyte differentiation, and especicallyto treat type 2 diabetes and other diseases are disclosed.

SUMMARY OF THE INVENTION

The present invention relates to certain substituted heterocycles whichare useful in the treatment of diseases related to lipid metabolism andadipocyte differentiation, such as type 2 diabetes; uncontrolledproliferation, such as lymphoma, Hodgkin's Disease, leukemia, breastcancer, prostate cancer, or cancers in general; and inflammation, suchas osteoarthritis, rheumatoid arthritis, Crohn's Disease, orInflammatory Bowel Disease.

Some disclosed embodiments of the invention relate to compounds of theFormula (I):

wherein:

n and m are independently 0 or 1;

R₁ and R₂ are 1) independently or together hydrogen, alkyl, substitutedalkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, alkoxy, substituted alkoxy, hydroxyl, acyl, amino,mono-substituted amino, di-substituted amino, carboxy, carboalkoxy,alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,substituted dialkylcarboxamide or haloalkoxy; or 2) R₁ and R₂ togetherwith the aromatic ring bonded thereto form a cycloalkyl, substitutedcycloalkyl, cycloalkenyl or substituted cycloalkenyl residue that mayoptionally comprise 1 or 2 heteroatoms selected from O, S, NH orN-alkyl;

R₃ and R₄ are independently or together hydrogen, alkyl, substitutedalkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino,mono-substituted amino, di-substituted amino, alkylsulfonamide,arylsulfonamide, alkylurea, arylurea, alkylcarbamate, arylcarbamate,heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl,thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide;

A is —CR₆R₇— where R₆ and R₇ are independently or together hydrogen,alkyl, substituted alkyl, alkoxy, substituted alkoxy or haloalkoxy; orR₆ and R₇ together form a cycloalkyl residue that may optionallycomprise 1 or 2 heteroatoms selected from O, S, NH and N-alkyl;

Ar is Formula (II), (III), (IV) or (V):

where R₈, R₉ and R₁₀ are independently or together hydrogen, alkyl,substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino,mono-substituted amino, di-substituted amino, alkylamide,alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate,arylcarbamate, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl,thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide;

R₅ is hydrogen, halogen, hydroxy, alkyl or substituted alkyl;

--- represents a bond present or absent; and

W, X, Y and Z are independently or together —C(O)—, —C(S)—, —S—, —O— or—NH-residues that together form a 2,4-thiazolidinedione,2-thioxo-4-thiazolidinedione, isoxazolidinedione, 2,4-imidazolidinedioneor 2-thioxo-4-imidazolidinedione residue; or a pharmaceuticallyacceptable salt thereof.

Other embodiments of the invention provide methods of synthesizing thecompounds of the invention.

In another aspect, this invention relates to the use of the compoundsdisclosed herein for modulating lipid metabolism, carbohydratemetabolism, lipid and carbohydrate metabolism, or adipocytedifferentiation; they are also useful for treating diseases ofuncontrolled cellular proliferation; and the treatment inflammatorydiseases.

This invention also relates to a method for modulating lipid metabolism,carbohydrate metabolism, lipid and carbohydrate metabolism or adipocytedifferentiation comprising administering to a mammal, preferably ahuman, diagnosed as needing such modulation, such as for the treatmentof type 2 diabetes. The invention also provides for a method oftreatment of a disease of uncontrolled cellular proliferation comprisingadministering to a mammal diagnosed as having a disease of uncontrolledcellular proliferation and a method of treating an inflammatory diseasecomprising administering to a mammal diagnosed as having an inflammatorydisease.

In another aspect, this invention relates to a pharmaceuticalcomposition comprising a compound disclosed herein in admixture with oneor more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1a shows the differentiation inducing activity of the compounds ofthe present invention in the absence of insulin.

FIG. 1b shows the differentiation inducing activity of the compounds ofthe present invention in the presence of insulin.

FIG. 2a shows the glucose lowering activity of Compound 1 in the db/dbMouse Model.

FIG. 2b shows the triglyceride lowering activity of Compound 1 in thedb/db Mouse Model.

FIG. 3a shows the glucose lowering activity of Compound 1 in the ob/obMouse Model.

FIG. 3b shows the triglyceride lowering activity of Compound 1 in theob/ob Mouse Model.

FIG. 4a shows the glucose lowering activity of Compound 32 in the db/dbMouse Model.

FIG. 4b shows the triglyceride lowering activity of Compound 32 in thedb/db Mouse Model.

FIG. 5 shows examples of methods for synthesizing the compoundsdisclosed herein wherein n is 0 and m is 1.

FIG. 6 shows examples of methods for synthesizing the compoundsdisclosed herein wherein n and m are 1.

FIG. 7 shows examples of methods for synthesizing the compoundsdisclosed herein wherein n is 0 or 1 and m is 0.

DETAILED DESCRIPTION

The present invention provides compounds that are useful, for example,to modulate lipid metabolism or adipocyte differentiation, andespecically for the treatment of diabetes, such as type 2 diabetes, andother diseases. Compounds disclosed herein are characterized byrelatively low molecular weight and may be used to treat diseases inrepresentative animal models such as those of type 2 diabetes. Inaddition, compounds of the invention have demonstrated oralbioavailability as exhibited by their high blood levels after oraldosing, either alone or in the presence of an excipient. Oralbioavailability allows oral dosing for use in chronic diseases, with theadvantage of self-administration and decreased cost over other means ofadministration. The compounds described herein may be used effectivelyto prevent, alleviate or otherwise treat type 2 diabetes and/or otherdisease states in mammals, including humans.

Definitions

In the specification and Formulae described herein the following termsare hereby defined.

The term “alkyl” denotes a radical containing 1 to 12 carbons, such asmethyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, amyl,t-amyl, n-pentyl and the like.

The term “alkenyl” denotes a radical containing 1 to 12 carbons such asvinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl, 2-heptenyl, 3-heptenyl,4-heptenyl, 5-heptenyl, 6-heptenyl and the like. The term “alkenyl”includes dienes and trienes of straight and branch chains.

The term “alkynyl” denotes a radical containing 1 to 12 carbons, such asethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 5-hexynyl and the like. The term “alkynyl”includes di- and tri-ynes.

The term “substituted alkyl” denotes a radical containing 1 to 12carbons of the above definitions that are substituted with one or moregroups, but preferably one, two or three groups, selected from hydroxyl,cycloalkyl, amino, mono-substituted amino, di-substituted amino,acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamide,substituted alkylcarboxamide, dialkylcarboxamide, substituteddialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl,thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy. When more thanone group is present then they may be the same or different.

The term “substituted alkenyl” denotes a radical containing 1 to 12carbons of the above definitions that are substituted with one or moregroups, but preferably one, two or three groups, selected from halogen,hydroxyl, cycloalkyl, amino, mono-substituted amino, di-substitutedamino, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamide,substituted alkylcarboxamide, dialkylcarboxamide, substituteddialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl,thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy. When more thanone group is present then they may be the same or different.

The term “substituted alkynyl” denotes a radical containing 1 to 8carbons of the above definitions that are substituted with one or moregroups, but preferably one or two groups, selected from halogen,hydroxyl, cycloalkyl, amino, mono-substituted amino, di-substitutedamino, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamide,substituted alkylcarboxamide, dialkylcarboxamide, substituteddialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl,thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy.

The term “cycloalkyl” denotes a radical containing 3 to 8 carbons, suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclopenyl, cyclohexyl,cycloheptyl and the like. The term “substituted cycloalkyl” denotes acycloalkyl as defined above that is further substituted with one or moregroups selected from halogen, alkyl, hydroxyl, alkoxy, substitutedalkoxy, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide,amino, mono-substituted amino or di-substituted amino. When thecycloalkyl is substituted with more than one group, they may be the sameor different.

The term “cycloalkenyl” denotes a radical containing 3 to 8 carbons,such as cyclopropenyl, 1-cyclobutenyl, 2-cyclobutenyl, 1-cyclopentenyl,2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl,3-cyclohexenyl and the like. The term “substituted cycloalkenyl” denotesa cycloalkenyl as defined above further substituted with one or moregroups selected from halogen, alkyl, hydroxyl, alkoxy, substitutedalkoxy, haloalkoxy, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide,amino, mono-substituted amino or di-substituted amino. When thecycloalkenyl is substituted with more than one group, they may be thesame or different.

The term “alkoxy” as used herein denotes a radical alkyl, defined above,attached directly to an oxygen such as methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, t-butoxy, iso-butoxy and the like.

The term “substituted alkoxy” denotes a radical alkoxy of the abovedefinition that is substituted with one or more groups, but preferablyone or two groups, selected from hydroxyl, cycloalkyl, amino,mono-substituted amino, di-substituted amino, acyloxy, nitro, cyano,carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide,dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl,alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy orhaloalkoxy. When more than one group is present then they may be thesame or different.

The term “mono-substituted amino” denotes an amino substituted with onegroup selected from alkyl, substituted alkyl or arylalkyl wherein theterms have the same definitions found throughout.

The term “di-substituted amino” denotes an amino substituted with tworadicals that may be same or different selected from aryl, substitutedaryl, alkyl, substituted alkyl or arylalkyl wherein the terms have thesame definitions found throughout. Some examples include dimethylamino,methylethylamino, diethylamino and the like.

The term “haloalkyl” denotes a radical alkyl, defined above, substitutedwith one or more halogens, preferably fluorine, such as atrifluoromethyl, pentafluoroethyl and the like.

The term “haloalkoxy” denotes a haloalkyl, as defined above, that isdirectly attached to an oxygen to form trifluoromethoxy,pentafluoroethoxy and the like.

The term “acyl” denotes a radical containing 1 to 8 carbons such asformyl, acetyl, propionyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl,heptanoyl, benzoyl and the like.

The term “acyloxy” denotes a radical containing 1 to 8 carbons of anacyl group defined above directly attached to an oxygen such asacetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxy, benzoyloxy andthe like.

The term “aryl” denotes an aromatic ring radical containing 6 to 10carbons that includes phenyl and naphthyl. The term “substituted aryl”denotes an aromatic radical as defined above that is substituted withone or more selected from hydroxyl, cycloalkyl, aryl, substituted aryl,heteroaryl, heterocyclic ring, substituted heterocyclic ring, amino,mono-substituted amino, di-substituted amino, acyloxy, nitro, cyano,carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide,dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl,alkylsulfinyl, alkylthio, alkoxy, substituted alkoxy or haloalkoxy,wherein the terms are defined herein.

The term “halo” or “halogen” refers to a fluoro, chloro, bromo or iodogroup.

The term “thioalkyl” denotes a sulfide radical containing 1 to 8carbons, linear or branched. Examples include methylsulfide, ethylsulfide, isopropylsulfide and the like.

The term “thiohaloalkyl” denotes a thioalkyl radical substituted withone or more halogens. Examples include trifluoromethylthio,1,1-difluoroethylthio, 2,2,2-trifluoroethylthio and the like.

The term “carboalkoxy” refers to an alkyl ester of a carboxylic acid,wherein alkyl has the same definition as found above. Examples includecarbomethoxy, carboethoxy, carboisopropoxy and the like.

The term “alkylcarboxamide” denotes a single alkyl group attached to theamine of an amide, wherein alkyl has the same definition as found above.Examples include N-methylcarboxamide, N-ethylcarboxamide,N-(iso-propyl)carboxamide and the like. The term “substitutedalkylcarboxamide” denotes a single “substituted alkyl” group, as definedabove, attached to the amine of an amide.

The term “dialkylcarboxamide” denotes two alkyl or arylalkyl groups thatare the same or different attached to the amine of an amide, whereinalkyl has the same definition as found above. Examples of adialkylcarboxamide include N,N-dimethylcarboxamide,N-methyl-N-ethylcarboxamide and the like. The term “substituteddialkylcarboxamide” denotes two alkyl groups attached to the amine of anamide, where one or both groups is a “substituted alkyl”, as definedabove. It is understood that these groups may be the same or different.Examples include N,N-dibenzylcarboxamide, N-benzyl-N-methylcarboxamideand the like.

The term “alkylamide” denotes an acyl radical attached to an amine ormonoalkylamine, wherein the term acyl has the same definition as foundabove. Examples of “alkylamide” include acetamido, propionamido and thelike.

The term “arylalkyl” defines an alkylene, such as —CH₂— for example,which is substituted with an aryl group that may be substituted orunsubstituted as defined above. Examples of an “arylalkyl” includebenzyl, phenethylene and the like.

A residue of a chemical species, as used in the specification andconcluding claims, refers to the moiety that is the resulting product ofthe chemical species in a particular reaction scheme or subsequentformulation or chemical product, regardless of whether the moiety isactually obtained from the chemical species. Thus, an ethylene glycolresidue in a polyester refers to one or more —OCH2CH2O— repeat units inthe polyester, regardless of whether ethylene glycol is used to preparethe polyester. Similarly, a 2,4-thiazolidinedione residue in a chemicalcompound refers to one or more -2,4-thiazolidinedione moieties of thecompound, regardless of whether the residue was obtained by reacting2,4-thiazolidinedione to obtain the compound.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “an aromatic compound” includes mixtures of aromaticcompounds.

Compositions

Some disclosed embodiments of the invention relate to the Formula (I):

wherein:

n and m are independently 0 or 1;

R₁ and R₂ are independently or together hydrogen, alkyl, substitutedalkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, alkoxy, substituted alkoxy, hydroxyl, acyl, amino,mono-substituted amino, di-substituted amino, carboxy, carboalkoxy,alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,substituted dialkylcarboxamide or haloalkoxy; or R₁ and R₂ together withthe aromatic ring form a cycloalkyl, substituted cycloalkyl,cycloalkenyl or substituted cycloalkenyl optionally comprising 1 or 2heteroatoms selected from O, S, NH and N-alkyl;

R₃ and R₄ are independently or together hydrogen, alkyl, substitutedalkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino,mono-substituted amino, di-substituted amino, alkylsulfonamide,arylsulfonamide, alkylurea, arylurea, alkylcarbamate, arylcarbamate,heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl,thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide;

A is —CR₆R₇— where R₆ and R₇ are independently or together hydrogen,alkyl, substituted alkyl, alkoxy, substituted alkoxy or haloalkoxy; orR₆ and R₇ together form a cycloalkyl comprising 1 or 2 heteroatomsselected from O, S, NH and N-alkyl;

Ar is Formula (II), (III), (IV) or (V):

where R₈, R₉ and R₁₀ are independently or together hydrogen, alkyl,substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino,mono-substituted amino, di-substituted amino, alkylamide,alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate,arylcarbamate, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl,thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide;

R₅ is hydrogen, halogen, hydroxy, alkyl or substituted alkyl;

--- represents a bond present or absent; and

W, X, Y and Z are independently or together —C(O)—, —C(S)—, —S—, —O— or—NH—, preferably such that they form a 2,4-thiazolidinedione,2-thioxo-4-thiazolidinedione, isoxazolidinedione, 2,4-imidazolidinedioneor 2-thioxo-4-imidazolidinedione residue. These residues can beillustrated by the following Formulae:

Any compound disclosed herein may optionally be formulated as apharmaceutically acceptable salt.

In some embodiments W, X, Y and Z are independently or together —C(O)—,—C(S)—, —S—, —O—, or —NH— to form a 2,4-thiazolidinedione,2-thioxo-4-thiazolidinedione, 2,4-imidazolidinedione or2-thioxo-4-imidazolidinedione residue.

In some embodiments n is 0; R₁ and R₂ are independently or togetheralkyl, substituted alkyl or hydroxyl; or R₁ and R₂ together with thearomatic ring bonded thereto form a substituted cycloalkyl optionallycomprising 1 or 2 heteroatoms selected from O, NH or N-alkyl;

In another embodiment R₃ and R₄ are independently or together halogen,alkyl, substituted alkyl, haloalkyl, alkoxy, substituted alkoxy, amino,mono-substituted amino, di-substituted amino or haloalkoxy.

In one embodiment R₅ is hydrogen, alkyl or substituted alkyl. In anotherembodiment, R₅ is hydrogen.

In another embodiment Ar is Formula (VI), (VII) or (VIII):

wherein:

R₈ is alkyl, substituted alkyl, alkenyl, haloalkyl, hydroxy, acyloxy,halogen, alkoxy, substituted alkoxy, amino, mono-substituted amino,di-substituted amino, alkylamide or haloalkoxy; and

R₉ and R₁₀ are independent or together hydrogen, halogen, alkyl,substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkoxy,hydroxyl, amino, mono-substituted amino, di-substituted amino,alkylamide or haloalkoxy.

In some embodiments --- represents a bond present and the compound is abenzylidene compound having the structural Formula:

In some embodiments ---- represents a bond absent and the compound is abenzyl compound having the structural Formula:

In another embodiment of the invention R₁ and R₂ together with thearomatic ring bonded thereto form a substituted cycloalkyl.

In still another embodiment R₃ is methyl, ethyl, trifluoromethyl,methoxy or dimethylamino; and R₄ is hydrogen.

In another embodiment R₁ and R₂ together with the aromatic ring bondedthereto form a substituted cycloalkyl; R₃ is methyl, ethyl,trifluoromethyl, methoxy or dimethylamino; and R₄ is hydrogen, to form apolycyclic residue. Preferred polycyclic residues may be selected from:

1) 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl:

2) 3-ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl:

3) 3-trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl:

4) 3-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl:

or

5) 3-dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl:

In some embodiments, R₁ and R₂ together with the aromatic ring ofFormula I form a substituted cycloalkyl residue having the5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl radical:

in another embodiment, R₁ and R₂ together with the aromatic ring ofFormula I form a substituted cycloalkyl optionally comprising 1 or 2nitrogen heteroatoms, to give a1-isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl radical;

or a 1,4-diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl radical:

In still another embodiment of the invention wherein the A group ispresent (i.e. n is 1), R₁ and R₂ together with the aromatic ring form acycloalkyl or substituted cycloalkyl optionally comprising 1 or 2nitrogen heteroatoms; R₃ is halogen, alkyl, substituted alkyl,haloalkyl, alkoxy, substituted alkoxy, haloalkoxy, amino,mono-substituted amino or di-substituted amino; R₆ and R₇ together forma cycloalkyl optionally comprising 1 or 2 oxygen heteroatoms, and W, X,Y and Z are independently or together —C(O)—, —C(S)—, —S— or —NH— toform a 2,4-thiazolidinedione, 2-thioxo-4-thiazolidinedione,2-thioxo-4-imidazolidinedione or 2,4-imidazolidinedione residue.

This invention also relates to a pharmaceutical formulation comprisingone or more compounds disclosed herein in an admixture with apharmaceutically acceptable excipient.

Compounds disclosed herein may exist in various tautomeric forms. Forexample, 2,4-thiazolidinedione-containing compounds disclosed herein mayexist in the form of tautomers (Xa), (Xb) and (Xc).

It is understood by those of skill in the art that tautomers may alsoexist with 2-thioxo-4-thiazolidinedione, 2,4-imidazolidinedione,2-thioxo-4-imidazolidinedione and isoxazolidinedione containingcompounds disclosed herein. For convenience, all of the tautomers may bepresented herein by a single formula, but it is understood that alltautomers are within the scope of the invention.

When --- is present both E and Z configurations are within the scope ofthe invention. For example, 2,4-thiazolidinedione and2-thioxo-4-thiazolidinedione of Formula (I) may have the followingstructures respectively:

The compounds disclosed herein may also include salts of the compounds,such as salts with cations. Cations with which the compounds of theinvention may form pharmaceutically acceptable salts include alkalimetals, such as sodium or potassium; alkaline earth metals, such ascalcium; and trivalent metals, such as aluminum. The only constraintwith respect to the selection of the cation is that it should notunacceptably increase the toxicity. Due to the tautomerism describedabove for the compounds, mono-,di- or tri-salts may be possibledepending on the corresponding alkali metal. Also, one or more compoundsdisclosed herein may include salts formed by reaction of a nitrogencontained within the compound, such as an amine, aniline, substitutedaniline, pyridyl and the like, with an acid, such as HCl, carboxylicacid and the like. Therefore, all possible salt forms in relationship tothe tautomers and a salt formed from the reaction between a nitrogen andacid are within the scope of the invention.

The present invention provides, but is not limited to, the specificcompounds set forth in the Examples as well as those set forth below,and a pharmaceutically acceptable salt thereof:

where n is 0, and --- is absent or present:

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzylidene)-2,4-thiazolidinedione,

5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylidene-2,4-thiazolidinedione,

6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2-thioxo-4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzylidene-2,4-thiazolidinedione,

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzylidene-2,4-thiazolidinedione,

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzylidene-2,4-thiazolidinedione,

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2,4-thiazolidinedione,

3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzylidene-2,4-thiazolidinedione,

3-(3,5-Di-t-butyl-4-hydroxyphenyl)-3-methoxybenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzylidene-2-thioxo-4-thiazolidinedione,

5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylidene-2-thioxo-4-thiazolidinedione,

6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylidene-2-thioxo-4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzylidene-2-thioxo-4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzylidene-2-thioxo-4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzylidene-2-thioxo-4-thiazolidinedione,

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzylidene-2-thioxo-4-thiazolidinedione,

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzylidene-2-thioxo-4-thiazolidinedione,

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2-thioxo-4-thiazolidinedione,

3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzylidene-2-thioxo-4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzylidene-2-thioxo-4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzylidene-2-thioxo-4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzylidene-2-thioxo-4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzylidene-2-thioxo-4-thiazolidinedione,

3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl]-2,4-thiazolidinedione,

3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzyl]-2,4-thiazolidinedione,

3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-dimethylaminobenzyl]-2,4-thiazolidinedione,

3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzyl)]-2,4-thiazolidinedione,

5-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylmethylene]-2,4-thiazolidinedione,

6-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylmethylene]-2,4-thiazolidinedione,

3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl]-2-thioxo-4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzyl-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzyl-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzyl-2,4-thiazolidinedione,

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzyl-2,4-thiazolidinedione,

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzyl-2,4-thiazolidinedione,

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl-2,4-thiazolidinedione,

3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzyl-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzyl-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzyl-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzyl-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzyl-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzyl-2-thioxo-4-thiazolidinedione,

5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylmethylene-2-thioxo-4-thiazolidinedione,

6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylmethylene-2-thioxo-4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzyl-2-thioxo-4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzyl-2-thioxo-4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzyl-2-thioxo-4-thiazolidinedione,

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzyl-2-thioxo-4-thiazolidinedione,

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzyl-2-thioxo-4-thiazolidinedione,

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl-2-thioxo-4-thiazolidinedione,

3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzyl-2-thioxo-4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzyl-2-thioxo-4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzyl-2-thioxo-4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzyl-2-thioxo-4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzyl-2-thioxo-4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2-thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzylidene-2-thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzylidene-2-thioxo-4-imidazolidinedione,

6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylidene-2-thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzylidene-2-thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzylidene-2-thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzylidene-2-thioxo-4-imidazolidinedione,

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzylidene-2-thioxo-4-imidazolidinedione,

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzylidene-2-thioxo-4-imidazolidinedione,

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2-thioxo-4-imidazolidinedione,

3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzylidene-2-thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzylidene-2-thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzylidene-2-thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzylidene-2-thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzylidene-2-thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2,4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzylidene-2,4-imidazolidinedione,

5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylidene-2,4-imidazolidinedione,

6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylidene-2,4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzylidene-2,4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzylidene-2,4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzylidene-2,4-imidazolidinedione,

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzylidene-2,4-imidazolidinedione,

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzylidene-2,4-imidazolidinedione,

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2,4-imidazolidinedione,

3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzylidene-2,4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzylidene-2,4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzylidene-2,4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzylidene-2,4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzylidene-2,4-imidazolidinedione,

3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl]-2-thioxo-4-imidazolidinedione,

3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzyl)]-2-thioxo-4-imidazolidinedione,

5-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylmethylene]-2-thioxo-4-imidazolidinedione,

6-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylmethylene]-2-thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzyl-2-thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzyl-2-thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzyl-2-thioxo-4-imidazolidinedione,

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzyl-2-thioxo-4-imidazolidinedione,

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzyl-2-thioxo-4-imidazolidinedione,

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl-2-thioxo-4-imidazolidinedione,

3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzyl-2-thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzyl-2-thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzyl-2-thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzyl-2-thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzyl-2-thioxo-4-imidazolidinedione,

3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl]-2,4-imidazolidinedione,

3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzyl)]-2,4-imidazolidinedione,

5-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylmethylene]-2,4-imidazolidinedione,

6-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylmethylene]-2,4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzyl-2,4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzyl-2,4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzyl-2,4-imidazolidinedione,

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzyl-2,4-imidazolidinedione,

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzyl-2,4-imidazolidinedione,

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl-2,4-imidazolidinedione,

3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzyl-2,4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzyl-2,4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzyl-2,4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzyl-2,4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzyl-2,4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-dimethylaminobenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-chlorobenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methylbenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-ethylbenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethylbenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-ethoxybenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-ethoxy-2-fluorobenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-isopropoxybenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-aminobenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-acetamidobenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-ethoxy-2,5-difluorobenzylidene-2,4-thiazolidinedione,

3-(3-Methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione,

3-(3-Dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione,

3-(3-Trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2,4-thiazolidinedione,

3-(3-Trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methylbenzylidene-2,4-thiazolidinedione,

3-(3-Trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-ethylbenzylidene-2,4-thiazolidinedione,

3-(3-Trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione,

3-(3-Dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-dimethylaminobenzylidene-2,4-thiazolidinedione,

3-(3-Trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-chlorobenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methylamino-5-bromobenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-acetoxybenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-hydroxybenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-(1-propen-3-yl)-benzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxy-5-fluorobenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxy-2,5-difluorobenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,6-difluorobenzylidene-2,4-thiazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5,6-difluorobenzylidene-2,4-thiazolidinedione,

3-(3-Trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-dimethylaminobenzylidene-2,4-thiazolidinedione,and

3-(3-Ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione.

The structures for these compounds are shown below:

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzylidene-2,4- thiazolidinedione

5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylidene-2,4- thiazolidinedione

6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2-thioxo-4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzylidene- 2,4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzylidene-2,4- thiazolidinedione

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxahnyl)-4-methoxybenzylidene-2,4- thiazolidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzylidene-2,4- thiazolidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2,4- thiazolidinedione

3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzylidene- 2,4-thiazolidinedione

3-(3,5-Di-t-butylphenyl)-4-methoxy- benzylidene-2,4-thiazolidinedione

4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-3-methoxybenzylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzylidene-2- thioxo-4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzylidene-2- thioxo-4-thiazolidinedione

5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylidene-2-thioxo- 4-thiazolidinedione

6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylidene-2-thioxo- 4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzylidene- 2-thioxo-4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzylidene-2-thioxo- 4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzylidene-2-thioxo- 4-thiazolidinedione

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzylidene-2-thioxo- 4-thiazolidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzylidene-2- thioxo-4-thiazolidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2-thioxo-4- thiazolidinedione

3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzylidene-2-thioxo- 4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzylidene-2-thioxo- 4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzylidene-2-thioxo-4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzylidene- 2-thioxo-4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzylidene-2-thioxo-4-thiazolidinedione

3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl]-2,4- thiazolidinedione

3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzyl)]-2,4- thiazolidinedione

5-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylmethylene]-2,4- thiazolidinedione

6-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylmethylene]-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl-2-thioxo-4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzyl-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzyl-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzyl-2,4- thiazolidinedione

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzyl-2,4- thiazolidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzyl-2,4- thiazolidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl-2,4- thiazolidinedione

3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzyl-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzyl-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzyl-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzyl-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzyl- 2,4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzyl- 2,4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzyl-2-thioxo- 4-thiazolidinedione

5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylmethylene-2- thioxo-4-thiazolidinedione

6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylmethylene-2- thioxo-4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzyl-2- thioxo-4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzyl-2-thioxo-4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzyl-2-thioxo-4- thiazolidinedione

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzyl-2-thioxo-4- thiazolidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzyl-2-thioxo-4- thiazolidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl-2-thioxo-4- thiazolidinedione

3 (1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzyl-2-thioxo-4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-dimethylaminobenzyl-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzyl-2-thioxo- 4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzyl-2-thioxo-4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzyl-2- thioxo-4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzyl- 2-thioxo-4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2-thioxo-4- imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzylidene-2- thioxo-4-imidazolidinedione

5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylidene-2-thioxo- 4-imidazolidinedione

6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylidene-2-thioxo- 4-imidazotidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzylidene- 2-thioxo-4-imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzylidene-2-thioxo- 4-imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzylidene-2-thioxo- 4-imidazolidinedione

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzylidene-2-thioxo- 4-imidazolidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzylidene-2- thioxo-4-imidazolidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2-thioxo-4- imidazolidinedione

3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzylidene-2-thioxo-4- imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzylidene-2-thioxo- 4-imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzylidene-2-thioxo-4- imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzylidene-2- thioxo-4-imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzylidene-2-thioxo-4-imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2,4- imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzylidene-2,4- imidazolidinedione

5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylidene-2,4- imidazolidinedione

6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylidene-2,4- imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzylidene- 2,4-imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-acetoxybenzylidene- 2,4-thizolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzylidene-2,4- imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzylidene-2,4- imidazolidinedione

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzylidene-2,4- imidazolidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzylidene-2,4- imidazolidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2,4- imidazolidinedione

3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzylidene-2,4- imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzylidene-2,4- imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzylidene-2,4- imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzylidene-2,4- imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzylidene- 2,4-imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-hydroxybenzylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-(1-propen-3-yl)-benzylidene-2,4- thiazolidinedione

3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl]-2-thioxo-4- imidazolidinedione

3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzyl)]-2- thioxo-4-imidazolidinedione

5-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylmethylene]-2- thioxo-4-imidazolidinedione

6-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylmethylene]-2- thioxo-4-imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy--hydroxybenzyl-2- thioxo-4-imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzyl-2-thioxo-4- imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzyl-2-thioxo-4- imidazolidinedione

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzyl-2-thioxo-4- imidazolidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzyl-2-thioxo-4- imidazolidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl-2-thioxo-4- imidazolidinedione

3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzyl-2-thioxo-4- imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxy-5-fluorobenzylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzyl-2-thioxo-4- imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzyl-2-thioxo-4- imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzyl-2-thioxo- 4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzyl-2- thioxo-4-imidazolidinedione,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,6-difluorobenzylidene- 2,4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxy-2,5-difluorobenzylidene- 2,4-thiazolidinedione

3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl]-2,4- imidazolidinedione

3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzyl)]-2,4- imidazolidinedione

5-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylmethylene]-2,4- imidazolidinedione

6-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylmethylene]-2,4- imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzyl-2,4- imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzyl-2,4- imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzyl-2,4- imidazolidinedion,

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzyl-2,4- imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzyl-2,4- imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzyl- 2,4-imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzylidene- 2,4-imidazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5,6-difluorobenzylidene- 2,4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzyl-2,4- imidazolidinedione

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzyl-2,4- imidazoiidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzyl-2,4- imidazolidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl-2,4- imidazolidinedione

3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzyl-2,4- imidazolidinedione

3-(3-Ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene- 2,4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-dimethylaminobenzylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-chlorobenzylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methylbenzylidene-2,4- thiazolidindione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-ethylbenzylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethylbenzylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-ethoxybenzylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-ethoxy-2-fluorobenzylidene-2,4- thiazolidinedione

3-(3-Trifluoro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-dimethylaminobenzylidene- 2,4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-isopropoxybenzylidene-2,4- thiazolidindione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-aminobenzylidene-2,4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-acetamidobenzylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-ethoxy-2,5-fluorobenzylidene-2,4- thiazolidinedione

3-(3-Methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxy- benzylidene-2,4-thiazolidinedione

3-(3-Dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione

3-(3-Trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene- 2,4-thiazolidinedione

3-(3-Trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methylbenzylidene-2,4- thiazolidinedione

3-(3-Trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-ethylbenzylidene-2,4- thiazolidinedione

3-(3-Trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxy-benzylidene-2,4-thiazolidinedione

3-(3-Dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-dimethylamino-benzylidene-2,4-thiazolidinedione

3-(3-Trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-chlorobenzylidene-2,4- thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methylamino-5-bromobenzylidene- 2,4-thiazolidinedione

In some embodiments of Formula (I) wherein A is present, (i.e. 0 when nis 1), R₁ and R₂ together with the aromatic ring form a substitutedcycloalkyl optionally comprising 1 or 2 nitrogen heteroatoms; and R₃ isalkyl or substituted alkyl. In other embodiments wherein A is —CR₆R₇—,R₆ and R₇ are independently or together alkyl; or R₆ and R₇ togetherform a substituted or unsubstituted cycloalkyl optionally comprising 1or 2 oxygen heteroatoms, or more preferably a 1,3-dioxolane ring. Stillwith respect to when n is 1, preferably W, X, Y and Z are independentlyor together —C(O)—, —C(S)—, —S— or —NH— to form a 2,4-thiazolidinedione,2-thioxo-4-thiazolidinedione, 2-thioxo-4-imidazolidinedione or2,4-imidazolidinedione.

Preferably when n=1, and --- represents the bond is present, thecompound is:

4-[2-(3,5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2,4-thiazolidinedione,

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2,4-thiazolidinedione,

4-[2-(3,5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2-thioxo-4-thiazolidinedione,

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2-thioxo-4-thiazolidinedione,

4-[2-(3,5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2-thioxo-4-imidazolidinedione,

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2-thioxo-4-imidazolidinedione,

4-[2-(3,5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2,4-imidazolidinedione;or

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2,4-imidazolidinedione.

In addition, when n=1, and --- represents the bond is absent, thecompound is:

4-[2-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2,4-thiazolidinedione,

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2,4-thiazolidinedione,

4-[2-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2-thioxo-4-thiazolidinedione,

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2-thioxo-4-thiazolidinedione,

4-[2-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2-thioxo-4-imidazolidinedione,

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2-thioxo-4-imidazolidinedione,

4-[2-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2,4-imidazolidinedione,or

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2,4-imidazolidinedione.

The structure for these compounds are showin below:

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2,4- thiazolidinedione

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2,4- thiazolidinedione

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2-thioxo- 4-thiazolidinedione

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2-thioxo- 4-thiazolidinedione

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2,4- thiazolidinedione

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2,4- thiazolidinedione

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2-thioxo-4- thiazolidinedione

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2-thioxo- 4-thiazolidinedione

4-[2-(3,5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2-thioxo-4- imidazolidinedione

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2-thioxo-4- imidazolidinedione

4-[2-(3,5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzylidene-2,4- imidazolidinedione

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzylidene-2,4- imidazolidinedione

4-[2-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2-thioxo-4- imidazolidinedione

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2-thioxo-4- imidazolidinedione

4-[2-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1,3-dioxolane]benzyl-2,4- imidazolidinedione

4-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-propyl]benzyl-2,4- imidazolidinedione

Making the Compositions

Various synthetic methods may be employed in the production of thecompounds disclosed herein. A representative set of synthetic pathwaysare shown in FIG. 5 for n=0. One method, for example, includes couplinga boronic acid of Formula (XX), R₁₄=H, with a carbonyl-containing arylbromide of Formula (XXI), R₁₅=Br, to give biaryl (XXIV) that issubstituted with a carbonyl group, preferably a formyl group (i.e.,R₅=H). Alternatively, boronic acid (XX) may be coupled with aryl bromide(XXV), R₁₅=Br, to give biaryl (XXVI) that is subsequently formylatedusing techniques known in the art, such as the Vilsmeier or theVilsmeier-Haack reaction, the Gatterman reaction, the Duff reaction, theReimer-Tiemann reaction or a like reaction. Coupling reactions such asthat described for the formation of Biaryl (XXIV) and (XXVI) may also beconducted using boronic esters, such as where R₁₄ together with theboron from a pinacol borate ester (formation of pinacol esters:Ishiyama, T., et al., J. Org. Chem. 1995, 60, 7508-7510, Ishiyama, T.,et al., Tetrahedron Letters 1997, 38, 3447-3450; coupling pinacolesters: Firooznia, F. et al., Tetrahedron Letters 1999, 40, 213-216,Manickam, G. et al., Synthesis 2000, 442-446; all four citationsencorporated herein by reference). In addition, R₁₅ may also be I, Cl ortriflate (derived from a phenol).

Biaryl (XXVI) may also be acylated, for example by the Friedel-CraftsAcylation reaction or the like. Preferably, biaryl (XXVI) is formylated.Alternatively, in a two step manner, biaryl (XXVI) is formylated byfirst performing a halogenation step to give biaryl (XXVII), such as abromination, followed by a halogen-metal exchange reaction using analkyl lithium and reaction with DMF or equivalent known in the art togive biaryl (XXIV) where R₅ is H. The carbonyl group of biaryl (XXIV)may subsequently be condensed with a heterocycle possessing an activemethylene moiety, such as 2,4-thiazolidinedione,2-thioxo-4-thiazolidinedione, isoxazolidinedione, 2,4-imidazolidinedioneor 2-thioxo-4-imidazolidinedione to give benzylidene (XXVIII). Thecarbonyl group of biaryl (XXIV) may also be reduced, such as with sodiumborohydride, to benzyl alcohol (XXIX, R₂₀=OH) and converted to benzylbromide (XXIX, R₂₀=Br) with HBr or some other method known in the art,such as PPh₃/CBr₄. Benzyl bromide (XXIX, R₂₀=Br) is allowed to reactwith the anion(s) of 2,4-thiazolidinedione to give biaryl [(XXX), where:W=—C(O)—, X=—NH—, Y=—C(O)— and Z=—S—]. Similarly, anions of otherheterocycles disclosed herein may be used. Alternative, biaryl [(XXX),where: W=—C(O)—, X=—NH—, Y=—C(O)— and Z=—S—] may be prepared by areduction of benzylidene [(XXVIII), where: W=—C(O)—, X=—NH—, Y=—C(O)—and Z=—S—] using methods known in the art, such as hydrogenation in thepresence of Pd/C, Mg/MeOH and the like.

In an alternative manner, the coupling may take place between aryl(XXII), such as where R₁₅=Br, and boronic acid (XXIII, R₁₄=H) to givethe above mention biaryl (XXIV). Also aryl (XXII) may be coupled withboronic acid (XXXI) to give biaryl (XXVI). Employing the same strategyas described above biaryl (XXVI) may be either formylated or acylated toachieve biaryl (XXIV).

In some embodiments of the invention provide a process for thepreparation of a compound of the Formula (XV):

wherein:

R₁ and R₂ are independently or together hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,alkoxy, substituted alkoxy, hydroxyl, acyl, amino, mono-substitutedamino, di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide,substituted alkylcarboxamide, dialkylcarboxamide, substituteddialkylcarboxamide or haloalkoxy; or R₁ and R₂ together with thearomatic ring form a cycloalkyl, substituted cycloalkyl, cycloalkenyl orsubstituted cycloalkenyl optionally comprising 1 or 2 heteroatomsselected from O, S, NH and N-alkyl;

R₃ and R₄ are independently or together hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino,di-substituted amino, alkylsulfonamide, arylsulfonamide, alkylurea,arylurea, alkylcarbamate, arylcarbamate, heteroaryl, alkoxy, substitutedalkoxy, haloalkoxy, thioalkyl, thiohaloalkyl, carboxy, carboalkoxy,alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide orsubstituted dialkylcarboxamide;

Ar is Formula (II), (III), (IV) or (V):

where R₈, R₉ and R₁₀ are independently or together hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino,mono-substituted amino, di-substituted amino, alkylamide,alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate,arylcarbamate, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl,thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide;R₁₁ is hydrogen, alkyl or substituted alkyl;

R₅ is hydrogen, halogen, hydroxy, alkyl or substituted alkyl;

----- represents a bond present or absent; and

W, X, Y and Z are independently or together —C(O)—, —C(S)—, —S—, —O— or—NH— residues that form a 2,4-thiazolidinedione,2-thioxo-4-thiazolidinedione, isoxazolidinedione, 2,4-imidazolidinedioneor 2-thioxo-4-imidazolidinedione residue;

comprising the steps of:

1) coupling a first aryl residue with a second aryl residue to give abiaryl carbonyl containing compound;

wherein the first aryl residue comprises a substituted or unsubstitutedresidue having the structure:

and wherein the second aryl residue has a carbonyl group and comprises asubstituted or unsubstituted residue having the structure:

and wherein the biaryl carbonyl containing compound comprises asubstituted or unsubstituted residue having the structure:

 and

2) condensing the biaryl carbonyl containing compound with an activemethylene compound of the structure:

In another embodiments of the invention provides a process furthercomprising the step of reducing the benzylidene of Formula (XV) to formthe benzyl compound of Formula (XVI):

A number of methods suitable for reducing benzylidene compounds tobenzyl compounds (including hydrogenation, reaction with metal hydridereagents, or dissolving metal reductions) are known to those of skill inthe art, and those methods may be applied in the methods of the instantinvention.

The various organic group transformations utilized herein may beperformed by a number of procedures other than those described above.References for other synthetic procedures that may be utilized for thesynthetic steps leading to the compounds disclosed herein may be foundin, for example, March, J., Advanced Organic Chemistry, 4^(th) Edition,Weiley-Interscience (1992); or Larock, R. C., Comprehensive OrganicTransformations, A Guide to Functional Group Preparations, VCHPublishers, Inc. (1989), both incorporated herein by reference.

One embodiment of the invention relates to the processes for makingcompounds of Formula I, where n is 0, which comprises coupling twoaromatic rings to give a biaryl wherein one of the aryl rings contains acarbonyl moiety, preferably an aldehyde. The resulting biaryl productmay be subsequently condensed with an active methylene compound, such as2,4-thiazolidinedione, 2-thioxo-4-thiazolidinedione,2,4-imidazolidinedione or 2-thioxo-4-imidazolidinedione to give abenzylidene compound of Formula (I) where ----- is a bond. In anoptional step, the benzylidene compound may be reduced to give a benzylcompound of Formula (I) where ----- is absent.

Coupling of two aryl rings may be conducted using an aryl boronic acidor esters with an aryl halide (such as, iodo, bromo, or chloro),triflate or diazonium tetrafluoroborate; as described respectively inSuzuki, Pure & Applied Chem., 66:213-222 (1994), Miyaura and Suzuki,Chem. Rev. 95:2457-2483 (1995), Watanabe, Miyaura and Suzuki, Synlett.207-210 (1992), Littke and Fu, Angew. Chem. Int. Ed., 37:3387-3388(1998), Indolese, Tetrahedron Letters, 38:3513-3516 (1997), Firooznia,et. al., Tetrahedron Letters 40:213-216 (1999), and Darses, et. al.,Bull. Soc. Chim. Fr. 133:1095-1102 (1996); all incorporated herein byreference. According to this coupling reaction, precursors such as (XX)and (XXI) may be employed:

where R₁₄ is either alkyl or hydrogen and R₁₅ is a halide (such as,iodo, bromo, or chloro), triflate or diazonium tetrafluoroborate.Alternately, it is understood that the coupling groups may be reversed,such as the use of (XXII) and (XXIII), to achieve the same couplingproduct:

where R₁₄ and R₁₅ have the same meaning as described above. Thepreparation of the above mentioned precursors may be prepared by methodsreadily available to those skilled in the art. For example, the boronicester may be prepared from an aryl halide by conversion into thecorresponding aryl lithium, followed by treatment with a trialkylborate. Preferably, the boronic ester is hydrolyzed to the boronic acid.

The coupling reaction may also be conducted between an arylzinc halideand an aryl halide or triflate. Alternately, the coupling reaction mayalso be executed using an aryl trialkyltin derivative and an aryl halideor triflate. These coupling methods are reviewed by Stanforth,Tetrahedron 54:263-303 (1998) and incorporated herein by reference. Ingeneral, the utilization of a specific coupling procedure is selectedwith respect to available precursors, chemoselectivity, regioselectivityand steric considerations.

Condensation of the biaryl carbonyl containing derivatives (e.g., FIG.5, compound (XXIV)) with a suitable active methylene compound, such as,2,4-thiazolidinedione, may be accomplished by the use of methods knownin the art. For example, the biaryl carbonyl product from the couplingreaction may be condensed with an active methylene compound to give abenzylidene compound of Formula (I) (i.e., ----- is a bond) as describedby Tietze and Beifuss, Comprehensive Organic Synthesis (Pergamon Press),2:341-394, (1991), incorporated herein by reference. It is understood bythose of skill in the art that intermediates having hydroxyl groupsbound thereto may be formed during condensation of a biaryl carbonylcontaining derivative and an active methylene compound, as shown below.

The hydroxyl groups of such intermediates are often eliminated (aswater) during the condensation reaction, to form the desired benzylidenecompound. Nevertheless, the conditions of the reaction may be modifiedfor the isolation or further use of hydroxyl containing intermediates,and such embodiments are within the scope of the invention. Although thereaction shown above depicts the formation of the condensationintermediate for the reaction between compound (XXIV) and an activemethylene compound, it is understood that a similar intermediate iswithin the scope of the invention for compounds (XLV) and (XLII).Effective catalysts for the condensation may be selected from ammonia,primary, secondary and tertiary amines, either as the free base or theamine salt with an organic acid, such as acetic acid. Examples ofcatalysts include pyrrolidine, piperidine, pyridine, diethylamine andthe acetate salts thereof. Inorganic catalysts may also be used for thecondensation. Inorganic catalysts include, but are not limited to,titanium tetrachloride and a tertiary base, such as pyridine; andmagnesium oxide or zinc oxide in an inert solvent system. This type ofcondensation can be strongly solvent-dependent and it is understood thatroutine experimentation may be necessary to identify the optimal solventwith a particular catalyst, preferable solvents include ethanol,tetrahydrofuran, dioxane or toluene; or mixtures thereof.

The active methylene compound of the present invention may be2,4-thiazolidinedione, 2-thioxo-4-thiazolidinone, 2,4-imidazolidinedioneor 2-thioxo-4-imidazolidinedione. The resulting benzylidene (e.g., FIG.5, compound (XXXIII)) may be reduced, if desired, to a compound ofFormula (I) wherein ----- is absent (e.g., FIG. 5, compound (XXX)).

In addition, various methods may be employed in the production of thecompounds disclosed herein wherein n=1, representative examples areshown in FIG. 6. Structures of compound (XL) may be prepared by methodsknown in the art. The acid, R₃₀=H or the ester, R₃₀=aryl, alkyl orsubstituted alkyl, may be reduced to the corresponding benzyl alcohol(XLI) followed by oxidation to an aldehyde (XLII). Alternatively, ester(XL), R₃₀=alkyl or substituted alkyl, may be reduced directly to thealdehyde via selective reductions, for example, DIBAL. Aldehyde (XLII)may be reacted with a metal reagent, such as a Grignard reagent, to givebenzyl alcohol (XLIV) that can subsequently be converted to ketone (XLV)via an oxidation, such as a Swern oxidation, Corey oxidation with NCS oranother suitable procedure described by Hudlicky, M, Oxidations inOrganic Chemistry, ACS Monograph 186 (1990), incorporated herein byreference. In a similar manner as described above, compound (XLII) orcompound (XLV) may be condensed with an active methylene of aheterocycle to give compound (XLVI). The reduced analogue (XLVII) may beprepared in a manner similar to the process described above using abenzyl halide derived from either benzyl alcohol (XLI) or reduction fromcompound (XLVI).

In addition, various methods may be employed in the production of thecompounds disclosed herein wherein n is either 0 or 1 and m is 0,representative examples are shown in FIG. 7. Utilizing, for example,compound (XLII) or (XXIV) the carbonyl may be converted to a cyanohydrinusing methods known in the art. Such methods include, the use of acetonecyanohydrin, TMS-CN/ZnI₂ (followed by hydrolysis of the TMS ether) andthe like. The resulting alcohol of the cyanohydrin may be converted to ahalide (where V=Cl or Br) with the use of thionyl chloride, thionylbromide or the like, in the presence or absence of solvent. Conversionto compounds of Formula where m is equal to 0 may be prepared by thereaction of the (XLII b) or (XXIV b) with thiourea followed byhydrolysis.

Using the Compositions

The compounds of the present invention have been found to be potentcompounds in a number of biological assays, both in vitro and in vivo,that correlate to, or are representative of, human diseases.

For instance, the compounds induce the differentiation of preadipocytesinto adipocytes. This activity (Harris and Kletzien, Mol. Pharmacol.,45:439-445 (1994); Willson et al., J. Med. Chem. 39:665-668 (1996)) hasbeen observed for certain compounds that have antidiabetic activity inhumans (Teboul et al., J. Biol. Chem. 270:28183-28187 (1995)). Examplesfor the adipocyte differentiation activity of the compounds of thepresent invention are shown in FIGS. 1a and 1 b (rosiglitazone,Avandia™, an insulin sensitizer approved for the treatment of type 2diabetes, is shown for comparison). FIG. 1a shows the differentiationactivity of the present invention without the presence of insulin,whereas FIG. 1b shows the differentiation activity in the presence ofinsulin. Both in the absence and presence of insulin, the disclosedcompounds increase lipid levels. The ability of the compounds to inducecells of the adipocyte lineage to differentiate may also correlate tothe ability of the compounds to treat or prevent other diseasesincluding such proliferative diseases as breast, prostate and othercancers.

The ability of the compounds to function as antidiabetic molecules maybe demonstrated in animal models for type 2 diabetes. In young db/dbmice, compound 1 is shown to prevent increases in glucose andtriglyceride levels when administered orally (FIGS. 2a, b). In anotheranimal model of type 2 diabetes, the ob/ob mouse, compound 1 is shown toreduce glucose and triglyceride levels (FIGS. 3a, b). In yet anotheranimal model of type 2 diabetes, diabetic db/db mice, compound 32 isshown to be equally or more potent than rosiglitazone in reducingglucose and triglyceride levels (FIGS. 4a and 4 b).

Compounds disclosed herein are useful, for example, to modulatemetabolism (such as, for example, lipid metabolism and carbohydratemetabolism) or adipocyte differentiation, and especially to treat type 2diabetes. Modulation of lipid metabolism, for example, would include anincrease of lipid content intracellularly or extracellularly. Modulationof lipid metabolism could also include a decrease of lipid contentintracellularly or extracellularly. Modulation of metabolism may occurdirectly for example, through binding of the compound of Formula I withits cognate nuclear receptor, which directly affects an increase ordecrease in lipid content by up-regulation or down-regulation of a geneinvolved in lipid metabolism. Modulation of metabolism may also occurindirectly, for example, through binding of the compound of Formula Iwith its cognate receptor, which up-regulates or down-regulates cellulardifferentiation or growth of cells that produce lipids, therebyindirectly causing lipid metabolism to be modulated. Modulation, forexample, could be an increase in lipid metabolism, such that lipidmetabolism is greater than that of a control. Modulation, also includes,for example, an increase in lipid metabolism, such that the lipidmetabolism approaches that of a control. Likewise, modulation of lipidmetabolism could be a decrease in lipid metabolism, such that the lipidmetabolism is less than or decreasing towards a control. Carbohydratemetabolism may also be up-regulated or down-regulated to either approachthe level of carbohydrate metabolism in a control or to deviate from thelevel of carbohydrate metabolism in a control. Changes in carbohydratemetabolism may directly or indirectly also result in changes of lipidmetabolism and, similarly, changes in lipid metabolism may lead tochanges in carbohydrate metabolism. An example is type 2 diabetes wherean increase in free fatty acids in the patients leads to decreasedcellular uptake and metabolism of glucose.

Performing an adipocyte differentiation assay, as described in Examples33 and 34, is one way to assay whether a compound indirectly increaseslipid content. In one disclosed embodiment, the compounds of Formula I,when the concentration of the compounds of Formula I is less than orequal to 10⁻⁶ M, will lead to the differentiation of preadipocytes intoadipocytes, of which the latter will have an increase in lipid content.

It is understood that a variety of lipid molecules may be modulated. Thecompounds disclosed herein may modulate a single type of lipid molecule,such as a triglyceride, or the compounds disclosed herein may modulatemultiple types of lipid molecules. The compounds disclosed herein mayalso modulate a single or variety of carbohydrate molecules. Thecompounds disclosed herein may modulate metabolism disorders, such astype 2 diabetes. Metabolism can be modulated by the compounds disclosedherein by, for example, decreasing the serum glucose levels and/ordecreasing the serum triglyceride levels, relative to a control havingserum glucose and/or triglyceride levels indicative of a mammal havingtype 2 diabetes. It is recognized that any decrease in serum glucoseand/or triglyceride levels can benefit the mammal having type 2diabetes.

These compounds may be characterized by their low molecular weights andphysiological stability, and therefore, represent a class that may beimplemented to prevent, alleviate, and/or otherwise, treat disorders oflipid and carbohydrate metabolism, such as obesity, dislipidemea, type 2diabetes and other diseases related to type 2 diabetes. It is understoodthat treatment or prevention of type 2 diabetes may involve modulationof lipid or carbohydrate metabolism, such as the modulation of serumglucose or serum triglyceride levels.

A preferred embodiment of the invention relates to the use of thecompounds disclosed herein. The compounds disclosed herein may be eitherused singularly or plurally, and pharmaceutical compositions thereof forthe treatment of mammalian diseases, particularly those related tohumans. Compounds disclosed herein and compositions thereof may beadministered by various methods including, for example, orally,enterally, parentally, topically, nasally, vaginally, ophthalinically,sublingually or by inhalation for the treatment of diseases related tolipid metabolism, carbohydrate metabolism, lipid and carbohydratemetabolism such as polycystic ovary syndrome, syndrome X, type 2diabetes, including disorders related to type 2 diabetes such as,diabetic retinopathy, neuropathy, macrovascular disease ordifferentiation of adipocytes. Routes of administration and doseagesknown in the art may be found in Comprehensive Medicinal Chemistry,Volume 5, Hansch, C. Pergamon Press, 1990; incorporated herein byreference. The compositions may also be used as regulators in diseasesof uncontrolled proliferation. The composition may be useful in thetreatment of polycystic kidney disease and cancers such as, carcinomas,lymphomas, leukemias, and sarcomas. A representative but non-limitinglist of cancers is lymphoma, Hodgkin's Disease, myeloid leukemia,bladder cancer, brain cancer, head and neck cancer, kidney cancer, lungcancers such as small cell lung cancer and non-small cell lung cancer,myeloma, neuroblastoma/glioblastoma, ovarian cancer, pancreatic cancer,prostate cancer, skin cancer, liver cancer, melanoma, colon cancer,cervical carcinoma, breast cancer, and epithelial cancer. Compoundsdisclosed herein may be used for the treatment of inflammatory diseasessuch as osteoarthritis, rheumatoid arthritis, Crohn's Disease, pulmonaryfibrosis, and Inflammatory Bowel Disease.

Although the compounds described herein may be administered as purechemicals, it is preferable to present the active ingredient as apharmaceutical composition. Thus another embodiment of is the use of apharmaceutical composition comprising one or more compounds and/or apharmaceutically acceptable salt thereof, together with one or morepharmaceutically acceptable carriers thereof and, optionally, othertherapeutic and/or prophylactic ingredients. The carrier(s) must be‘acceptable’ in the sense of being compatible with the other ingredientsof the composition and not overly deleterious to the recipient thereof.

Pharmaceutical compositions include those suitable for oral, enteral,parental (including intramuscular, subcutaneous and intravenous),topical, nasal, vaginal, ophthalinical, sublingually or by inhalationadministration. The compositions may, where appropriate, be convenientlypresented in discrete unit dosage forms and may be prepared by any ofthe methods well known in the art of pharmacy. Such methods include thestep of bringing into association the active compound with liquidcarriers, solid matrices, semi-solid carriers, finely divided solidcarriers or combination thereof, and then, if necessary, shaping theproduct into the desired delivery system.

Pharmaceutical compositions suitable for oral administration may bepresented as discrete unit dosage forms such as hard or soft gelatincapsules, cachets or tablets each containing a predetermined amount ofthe active ingredient; as a powder or as granules; as a solution, asuspension or as an emulsion. The active ingredient may also bepresented as a bolus, electuary or paste. Tablets and capsules for oraladministration may contain conventional excipients such as bindingagents, fillers, lubricants, disintegrants, or wetting agents. Thetablets may be coated according to methods well known in the art., e.g.,with enteric coatings.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may contain conventionaladditives such as suspending agents, emulsifying agents, non-aqueousvehicles (which may include edible oils), or one or more preservative.

The compounds may also be formulated for parenteral administration(e.g., by injection, for example, bolus injection or continuousinfusion) and may be presented in unit dose form in ampules, pre-filledsyringes, small bolus infusion containers or in multi-does containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, andmay contain formulatory agents such as suspending, stabilizing and/ordispersing agents. Alternatively, the active ingredient may be in powderform, obtained by aseptic isolation of sterile solid or bylyophilization from solution, for constitution with a suitable vehicle,e.g., sterile, pyrogen-free water, before use.

For topical administration to the epidermis, the compounds may beformulated as ointments, creams or lotions, or as the active ingredientof a transdermal patch. Suitable transdermal delivery systems aredisclosed, for example, in Fisher et al. (U.S. Pat. No. 4,788,063,incorporated herein by reference) or Bawa et al. (U.S. Pat. Nos.4,931,279, 4,668,506 and 4,713,244; all incorporated herein byreference). Ointments and creams may, for example, be formulated with anaqueous or oily base with the addition of suitable thickening and/orgelling agents. Lotions may be formulated with an aqueous or oily baseand will in general also contain one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. The active ingredient may also be deliveredvia iontophoresis, e.g., as disclosed in U.S. Pat. Nos. 4,140,122,4,383,529, or 4,051,842; incorporated herein by reference.

Compositions suitable for topical administration in the mouth includeunit dosage forms such as lozenges comprising active ingredient in aflavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; mucoadherent gels, and mouthwashescomprising the active ingredient in a suitable liquid carrier.

When desired, the above-described compositions may be adapted to providesustained release of the active ingredient employed, e.g., bycombination thereof with certain hydrophilic polymer matrices, e.g.,comprising natural gels, synthetic polymer gels or mixtures thereof.

The pharmaceutical compositions according to the invention may alsocontain other adjuvants such as flavorings, coloring, antimicrobialagents, or preservatives.

It will be further appreciated that the amount of the compound, or anactive salt or derivative thereof, required for use in treatment willvary not only with the particular salt selected but also with the routeof administration, the nature of the condition being treated and the ageand condition of the patient and will be ultimately at the discretion ofthe attendant physician or clinician.

In general, one of skill in the art understands how to extrapolate invivo data obtained in a model organism, such as an ob/ob or db/db mouse,to another mammal, such as a human. These extrapolations are not simplybased on the weights of the two organisms, but rather incorporatedifferences in metabolism, differences in pharmacological delivery, andadministrative routes. Based on these types of considerations, asuitable dose will, in alternative embodiments, typically be in therange of from about 0.5 to about 100 mg/kg/day, from about 1 to about 75mg/kg of body weight per day, from about 3 to about 50 mg per kilogrambody weight of the recipient per day, or in the range of 6 to 90mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.

The compound is conveniently administered in unit dosage form; forexample, in alternative embodiments, containing 0.5 to 1000 mg, 5 to 750mg, most conveniently, or 10 to 500 mg of active ingredient per unitdosage form.

One skilled in the art will recognize that dosage and dosage formsoutside these typical ranges can be tested and, where appropreiate, beused in the methods of this invention.

In separate embodiments, the active ingredient may be administered toachieve peak plasma concentrations of the active compound of from about0.5 to about 75 μM, about 1 to 50 μM, or about 2 to about 30 μM. Thismay be achieved, for example, by the intravenous injection of a 0.05 to5% solution of the active ingredient, optionally in saline, or orallyadministered as a bolus containing about 0.5-500 mg of the activeingredient. Desirable blood levels may be maintained by continuousinfusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusionscontaining about 0.4-15 mg/kg of the active ingredients.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart to which the invention pertains and as may be applied to theessential features hereinbefore set forth, and as follows in the scopeof the appended claims.

The following examples are given to illustrate the invention and are notintended to be inclusive in any manner:

EXAMPLES Example 13-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2,4-thiazolidinedione,Also Referred to as Compound 1 Herein:

To a solution of toluene (200 mL) containing piperidine (0.6 mL) andacetic acid (0.6 mL) was added4-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthylen-2-yl)benzaldehyde(20.3 g, 60.2 mmol) and 2,4-thiazolidinedione (7.0 g, 60.2 mmol) and thesolution was heated at reflux for 6 hours with continuous removal ofwater using a Dean-Stark water separator. The reaction mixture wascooled to room temperature, and the resulting crystalline compound wasfiltered and washed with water (150 mL). The yellow solid was taken upin a mixture of ethanol (50 mL) and water (300 mL), filtered, furtherwashed with water (500 mL) and dried to afford 21.0 g of5-[4-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzylidene]thiazolidine-2,4-dione(80%). The toluene filtrate was concentrated under reduced pressure andthe residue chromatographed on silica gel (Biotage, 2% methanol indichloromethane) to give 2.5 g more of product (9.7%); total yield89.7%.

¹H NMR (500 MHz; DMSO-d₆): δ1.22 (s, 6H); 1.27 (s, 6H); 1.65 (s, 4H);2.01 (s, 3H); 3.80 (s, 3H); 7.03 (s, 1H); 7.17 (s, 1H); 7.23 (d, J=8.7Hz, 1H); 7.32 (d, J=2.4 Hz, 1H); 7.60 (dd, J₁=8.7 Hz, J₂=2 Hz, 1H); 7.78(s, 1H); 12.5 (br, 1H).

¹H NMR (500 MHz; CDCl₃): δ1.27 (s, 6H); 1.32 (s, 6H); 1.70 (s, 4H); 2.10(s, 3H); 3.83 (s, 3H); 7.03 (d, J=8.4 Hz, 1H); 7.09 (s, 1H); 7.16 (s,1H); 7.33 (d, J=2 Hz, 1H); 7.48 (dd, J₁=8.6 Hz, J₂=2 Hz, 1H); 7.83 (s,1H). ¹³C NMR (125 MHz; DMSO-d₆): δ19.2; 31.6; 33.5; 33.6; 34.7; 55.6;111.9; 120.9; 125.5; 127.3; 127.7; 131.0; 131.2; 131.6; 132.9; 134.6;141.5; 143.4; 158.1; 167.9; 168.1.

The intermediate4-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzaldehydewas prepared as follows:

a. (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid

The (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)boronicacid, was prepared in an analogous manner as reported by Dawson et al.(J. Med. Chem. 1995, 38, 3368-3383).

b.3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-methoxybenzaldehyde

A mixture of 3-bromo-4-methoxybenzaldehyde (19.0 g, 88.4 mmol),(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid(23.8 g, 97.2 mmol) and potassium carbonate (48.8 g, 353.6 mmol) in1,2-dimethoxyethane (500 mL) and water (40 mL) was degassed with argonfor 60 minutes. Tetrakis(triphenylphosphine)palladium(0) (5.0 g, 4.3mmol) was added and the mixture heated at reflux under argon for 16hours. The solution was cooled to room temperature, diluted with ethylacetate (200 mL) and washed successively with water (100 mL) and brine(100 mL), dried over anhydrous magnesium sulfate, filtered andevaporated. The residue was chromatographed on silica gel (eluent: ethylacetate/hexane, 1:9) to give 26.8 g of3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-methoxy-benzaldehyde(90%). ¹H NMR (500 MHz; CDCl₃): δ1.26 (s, 6H); 1.32 (s, 6H); 1.70 (s,4H); 2.08 (s, 3H); 3.89 (s, 3H); 7.06 (d, J=8.5 Hz, 1H); 7.09 (s, 1H);7.16 (s, 1H); 7.71 (d, J=2.0 Hz, 1H); 7.88 (dd, J₁=2.0 Hz, J₂=8.5H (s,1H).

Example 23-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2-thioxo-4-thiazolidinedione,Also Referred to as Compound 2 Herein

To a mixture of 2-thioxo-4-thiazolidine (199 mg, 1.49 mmol), piperidine(0.05 mL, 0.49 mmol) and acetic acid (0.05 mL, 0.89 mmol) in dry toluene(20 mL) was added3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-methoxy-benzaldehyde(500 mg, 1.49 mmol). The reaction mixture was heated under reflux for 22hours, allowed to cool to room temperature and extracted with ethylacetate (2×75 mL). The organic extracts were successively washed withwater (50 mL), saturated aqueous NH₄Cl (50 mL), saturated aqueous NaCl(100 mL), dried over MgSO₄ and filtered. Removal of the solvent underreduced pressure gave a yellow solid which was purified by columnchromatography, using a Biotage 40S cartridge, eluting with 15% ethylacetate/85% hexane. The title compound was isolated as a bright yellowsolid (394 mg, 60%).

¹H NMR (500 MHz, DMSO-d₆): δ1.27 and 1.23 (12H), 1.65 (s, 4H), 2.02 (s,3H), 3.82 (s, 3H), 7.04 (s, 1H), 7.18 (s, 1H), 7.26 (d, J=8.7 Hz, 1H),7.33 (d, J=2.5 Hz, 1H), 7.62 (dd, J₁=6.2 Hz, J₂=2.5 Hz, 1H), 7.67 (s,1H), 13.75 (s, 1H).

Example 35-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylidene-2,4-thiazolidinedione

Prepared similar to Example 1 in 63% yield using2-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridine-5-carboxaldehyde.

¹H NMR (500 MHz, DMSO-d₆): δ1.22 (s, 6H), 1.27 (s, 6H), 1.64 (s, 4H)2.03 (s, 3H), 3.90 (s, 3H), 7.10 (s, 1H), 7.21 (s, 1H), 7.67 (d, J=2.2Hz, 1H), 7.84 (s, 1H), 8.47 (d, J=2.1 Hz, 1H), 12.65 (s, 1H).

The intermediate2-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridine-5-carboxaldehydewas prepared as follows:

a. 5-Bromo-2-methoxy-pyridine

To a suspension of 2-methoxypyridine (10.00 g, 0.09 mol) and sodiumacetate (8.27 g, 0.10 mmol) in 30 mL of glacial acetic acid was added asolution of bromine in 20 mL glacial acetic acid while maintaining thereaction temperature below 50° C. After 3 hours, 100 mL of H₂O was addedand the resulting solution neutralized with cold 2.5 M NaOH. Thesuspension was extracted with ether (2×200 mL), the combined organicswere dried over MgSO₄, filtered and evaporated. The crude material waspurified on silica gel (eluent: hexane to hexane:ethyl acetate 97:3) anddistilled (34-36.5° C./0.05 mm Hg) to give 8.84 g (51.3%) of5-bromo-2-methoxy-pyridine as a clear colorless liquid.

b. 2-methoxy-pyridine-5-carboxaldehyde

To a solution of 5-bromo-2-methoxy-pyridine (8.50 g, 45.2 mmol) in 100mL dry ether under argon at −64° C. was added 1.6 M n-BuLi in hexanes.The resulting mixture was stirred at −64° C. for 40 minutes and allowedto warm to −35° C. To the resulting suspension was added 7.0 mL of dryDMF over 10 minutes. After 15 minutes, the mixture was allowed to warmto 0° C. and 75 mL of 5% NH₄Cl was added. The resulting mixture wasseparated and the aqueous layer extracted with EtOAc (3×75 mL). Theorganics were combined, dried (MgSO₄), filtered and evaporated undervacuum to give 2-methoxy-pyridine-5-carboxaldehyde as a tannish solid(recrystallized from hexane), 3.76 g (60.6%); m.p. 48.5-50° C.

c. 2-methoxy-3-bromo-pyridine-5-carboxyaldehyde

To a suspension of 2-methoxypyridine-5-carboxyaldehyde (3.50 g, 25.5mmol) and sodium acetate (2.30 g, 28.1 mmol) in 15 mL of glacial aceticacid was added a solution of bromine (1.45 mL, 28.1 mmol) in 20 mLglacial acetic acid and the resulting mixture heated to 100° C. for 18hours under argon. The mixture was cooled, diluted with water (50 mL)and neutralized with 2.0 M NaOH. The resulting mixture was extractedwith ether (4×200 mL), the combined organics dried (MgSO₄), filtered andevaporated. The crude material was purified on silica gel [gradient,hexane:ethyl acetate (99:1) to hexane:ethyl acetate (92:8)] to give2-methoxy-3-bromo-pyridine-5-carboxyaldehyde as a white solid, 0.97 g(17.6%). ¹H NMR (500 MHz, CDCl₃): δ4.11 (s, 3H), 8.29 (d, J=2.0 Hz, 1H),8.56 (d, J=2.0 Hz, 1H), 9.92 (s, 1H).

d.2-Methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridine-5-carboxaldehyde

A mixture of 2-methoxy-3-bromo-pyridine-5-carboxyaldehyde (319 mg, 1.48mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)boronicacid (545 mg, 2.22 mmol), potassium carbonate (817 mg, 5.91 mmol) andwater (2 mL) in anhydrous 1,2-dimethoxyethane (30 mL) was degassed withargon for 15 minutes prior to the addition oftetrakis(triphenylphosphine)palladium (0) (342 mg, 0.30 mmol). Thereaction mixture was heated under reflux for 15 hours, allowed to coolto room temperature and extracted with ethyl acetate (2×100 mL). Theorganic extracts were successively washed with water (100 mL), asaturated aqueous solution of NH₄Cl (100 mL), a saturated aqueoussolution of NaCl (100 mL), dried over MgSO₄ and filtered. Removal of thesolvent under reduced pressure gave an oil which was purified by columnchromatography, using a Biotage 12M cartridge, eluting with 5% ethylacetate/95% hexane. The title compound was isolated in quantitativeyield.

¹H NMR (500 MHz, CDCl₃): δ1.24 (s, 6H), 1.27 (s, 6H), 1.70 (s, 4H), 2.09(s, 3H), 4.09 (s, 3H), 7.07 (s, 1H), 7.17 (s, 1H), 7.94 (d, J=2.0 Hz,1H), 8.64 (d, J=2.0 Hz, 1H), 10.01 (s, 1H).

Example 43-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzylidene-2,4-thiazolidinedione,Also Referred to as Compound 4 Herein

Prepared similar to Example 1 in a 57% yield using3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzaldehyde.

¹H NMR (500 MHz; CDCl₃): δ1.25 (s, 6H); 1.32 (s, 6H); 1.69 (s, 4H); 2.06(s, 3 H); 3.83 (s, 3H); 6.88 (d, J=8.5 Hz, 1H); 7.05 (s, 1H); 7.18 (s,1H); 7.47 (t, J=8.5 Hz, 1H); 8.08 (s, 1H).

The intermediate3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzaldehydewas prepared as follows:

a. 2-Fluoro-3-hydroxy-4-methoxybenzaldehyde

To a heated solution (80° C.) of hexamethylenetetramine (2.8 g, 20 mmol)in trifluoroacetic acid (10 mL) was added dropwise over a 50 minutesperiod 2-fluoro-6-methoxyphenol (1.42 g, 10 mmol) in trifluoroaceticacid (10 mL). The mixture was heated for an additional 1 hour,concentrated and water (50 ml) was added. The solution was stirred for10 minutes and solid potassium carbonate was added until the solutionwas neutral. The solid that formed was collected to afford 1.1 g of2-fluoro-3-hydroxy-4-methoxybenzaldehyde (65%). ¹H NMR (500 MHz;DMSO-d₆): δ3.90 (s, 3H); 6.98 (d, J=8.5 Hz, 1H); 7.31 (t, J=8.5 Hz, 1H);9.66 (br, 1H); 10.02 (s, 1H).

b. 2-Fluoro-4-methoxy-3-trifluoromethanesulfonyl benzaldehyde

To a solution of 2-fluoro-3-hydroxy-4-methoxybenzaldehyde (1.1 g, 6.47mmol) in dichloromethane (50 mL) was added pyridine (0.6 mL, 7.76 mmol)and the solution cooled to 0° C. Triflic anhydride (1.3 mL, 7.76 mmol)was added slowly and the reaction mixture warmed slowly to roomtemperature and stirred overnight at room temperature. The solution waswashed successively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated. The residue was chromatographed andsilica gel (eluent: ethyl acetate/hexane, 1:4) to give 1.21 g of2-fluoro-4-methoxy-3-trifluoromethanesulfonyl benzaldehyde (62%). ¹H NMR(500 MHz; CDCl₃): δ4.03 (s, 3H), 6.95 (d, J=8.0 Hz, 1H), 7.89 (dd, J=8.0Hz, J₂=9.0 Hz, 1H), 10.20 (s, 1H).

c. 2-Fluoro-4-methoxy-3-trifluoromethanesulfonyl benzaldehyde

A mixture of 2-fluoro-4-methoxy-3-trifluoromethanesulfonyl benzaldehyde(1.21 g, 4.01 mmol),(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid(1.08 g, 4.41 mmol) and potassium carbonate (2.22 g, 16.04 mmol) in1,2-dimethoxyethane (30 mL) and water (2 mL) was degassed with argon for30 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.2 mmol)was added and the mixture heated at reflux under argon for 16 hours. Thesolution was cooled to room temperature, diluted with ethyl acetate andwashed successively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated. The residue was chromatographed onsilica gel (Biotage, eluent: ethyl acetate/hexane, 0.5:8.5) to give 0.87g of4-methoxy-2-fluoro-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzaldehyde(62%). ¹H NMR (500 MHz; CDCl₃): δ1.26 (s, 6H), 1.32 (s, 6H), 1.69 (s,4H), 2.07 (s, 3H), 3.85 (s, 3H), 7.07 (d, J=8.8 Hz, 1H), 7.07 (s, 1H),7.19 (s, 1H), 7.90 (t, J=8.8 Hz, 1H), 10.25 (s, 1H).

Example 56-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylidene-2,4-thiazolidinedione

Prepared similar to Example 1 in a 21% yield using6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-5-methoxy-pyridine-2-carboxaldehyde.

¹H NMR (500 MHz; CDCl₃): δ1.32 (s, 6H); 1.34 (s, 6H); 1.72 (s, 3H); 2.18(s, 3 H); 3.87 (s, 3H); 7.18 (s, 1H); 7.30 (d, J=8.4 Hz, 1H); 7.40 (s,1H); 7.50 (d, J=8.5 Hz, 1H); 7.77 (s, 1H).

The intermediate6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphth-2-yl)-5-methoxy-pyridine-2-carboxaldehydewas prepared as follows:

a. 2-Bromo-3-hydroxy-6-methyl-pyridine

To a solution of 5-hydroxy-2-methylpyridine (8.80 g, 80.6 mmol) in 125mL of pyridine was added a solution of bromine (14.18 g, 88.7 mmol) in50 mL pyridine dropwise. The temperature of the reaction mixture rose to40° C. upon completion of addition. After 1 hour the pyridine wasremoved under vacuum and the resulting solid was suspended into water(200 mL) and stirred overnight. The solid was collected and dried togive the desire product as a brownish solid (8.05 g, 53.1% yield). ¹HNMR (500 MHz, CDCl₃): δ2.21 (s, 3H), 6.73 (d, J=8.1 Hz, 1H), 6.94 (d,J=8.1 Hz, 1H), 9.36 (brs, 1H).

b. 2-Bromo-3-methoxy-6-methyl-pyridine

A stirred mixture of 2-bromo-3-hydroxy-6-methyl-pyridine (7.89 g, 42.0mmol), potassium carbonate (11.60 g, 83.9 mmol) and iodomethane (8.93 g,62.9 mmol, 3.92 mL) in acetone (100 mL) was heated under refluxovernight. The mixture was filtered, evaporated and purified on silicagel (hexane:ethyl acetate, 95:5 to 9:1) to give the desired product as awhite solid (7.49 g, 88.3%). ¹H NMR (500 MHz, CDCl₃): δ2.46 (s, 3H),3.87 (s, 3H), 7.04 (s, 2H).

c. 5-Methoxy-6-bromo-pyridine-2-carboxaldehyde

A stirred mixture of 2-bromo-3-methoxy-6-methyl-pyridine (2.00 g, 9.9mmol), Cu(II) sulfate pentahydrate (2.47 g, 9.9 mmol), and potassiumperoxydisulfate (8.03 g, 29.7 mmol) in 80 mL of acetonitrile/H₂O (1:1)was heated under reflux. After 1 hour, the dark green mixture was cooledto room temperature and CH₂Cl₂ was added. The layers were separated andthe aqueous layer further extracted with CH₂Cl₂. The organics werecombined, dried (MgSO₄), filtered and evaporated. The resulting crudeproduct was purified on silica gel [Biotage, hexane:ethyl acetate (4:1)]to give a white solid (0.51 g, 24% yield).

d.6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphth-2-yl)-5-methoxy-pyridine-2-carboxaldehyde

A mixture of 6-bromo-5-methoxypyridine-2-carboxaldehyde (512 mg, 2.37mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)boronicacid (700 mg, 2.84 mmol) and potassium carbonate (1.31 g, 9.5 mmol) in1,2-dimethoxyethane (22 mL) and water (2 mL) was degassed with argon.Tetrakis(triphenylphosphine) palladium(0) (550 mg, 0.48 mmol) was addedand the mixture heated under reflux under argon for 24 hours. Thesolution was cooled to room temperature, diluted with ethyl acetate andwashed successively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated. The residue was chromatographed onsilica gel (Biotage hexane:EtOAc 9: 1) to give 603 mg (75% yield) of6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphth-2-yl)-5-methoxy-pyridine-2-carboxaldehyde.

¹H NMR (500 MHz; CDCl₃): δ1.29 (s, 6H), 1.31 (s, 6H), 1.70 (s, 4H), 2.15(s, 3H), 3.90 (s, 3H), 7.20 (s, 1H), 7.27 (s, 1H), 7.37 (d, J=8.5 Hz,1H), 8.00 (d, J=8.5 Hz, 1H), 10.04 (s, 1H).

Example 63-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzylidene-2,4-thiazolidinedione

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzylidene-2,4-thiazolidinedionemay be prepared in a similar manner as described in Example 1 using3-(1,4-diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzaldehyde.

The intermediate3-(1,4-diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzaldehydewas prepared as follows:

a. 6-Methyl-1,2,3,4-tetrahydroquinoxaline

To a solution of 6-methylquinoxaline (2 g, 13.87 mmol) and nickel (II)chloride hexahydrate (6.6 g, 27.74 mmol) in anhydrous methanol (70 mL)was added in portions, sodium borohydride (10.5 g, 277.43 mmol) whilemaintaining the temperature between 0° C. and 5° C. The reaction mixturewas stirred at 0° C. for 20 minutes and at room temperature for 4 hours.Removal of the solvent under reduced pressure was ensued byacidification of the residue with 2N HCl (600 mL). The mixture wasstirred at room temperature for 16 hours and filtered. The greenfiltrate was made basic (pH 10-11) using concentrated NH₄OH (150 mL) andextracted with diethylether (3×200 mL). The ethereal extracts weresuccessively washed with water (2×300 mL), a saturated aqueous solutionof NaCl (150 mL), dried over MgSO₄ and filtered. Removal of the solventunder reduced pressure gave 6-methyl-1,2,3,4-tetrahydroquinoxaline as asolid (880 mg, 43%).

¹H NMR (500 MHz; CDCl₃): δ2.17 (s, 3H), 3.39-3.40 (m, 4H), 6.41-6.33 (m,3 H).

b. 1,4-diisopropyl-6-methyl-1,2,3,4-tetrahydroquinoxaline

A mixture of 6-methyl-1,2,3,4-tetrahydroquinoxaline (851 mg, 5.75 mmol),potassium carbonate (3.18 g, 23 mmol) and 2-iodopropane (4.6 mL, 46mmol) in dry dimethylformamide (10 mL) was heated under reflux for 19hours, allowed to cool to room temperature prior to the addition ofwater (100 mL) and extracted with ethyl acetate (2×75 mL). The organicextracts were successively washed with a saturated aqueous solution ofNH₄Cl (100 mL), a saturated aqueous solution of NaCl (100 mL), driedover MgSO₄ and filtered. Removal of the solvent under reduced pressuregave a dark orange oil which was purified by column chromatography,using a Biotage 40S cartridge, eluting with 5% ethyl acetate/95% hexane,to give 1,4-diisopropyl-6-methyl-1,2,3,4-tetrahydroquinoxaline as asolid (870 mg, 66%).

¹H NMR (500 MHz; CDCl₃): δ1.19-1.16 (m, 12H), 2.24 (s, 3H), 3.16-3.14(m, 2H), 3.23-3.21 (m, 2H), 4.02 (quintet, J=6.5 Hz, 1H), 4.08 (quintet,J=6.5 Hz, 1H) 6.44 (d, J=8.0 Hz, 1H), 6.49 (s, 1H), 6.56 (d, J=8.1 Hz,1H).

c. 7-Bromo-1,4-diisopropyl-6-methyl-1,2,3,4-tetrahydroquinoxaline

A mixture of 1,4-diisopropyl-6-methyl-1,2,3,4-tetrahydroquinoxaline (516mg, 2.22 mmol) and tetrabutylammonium tribromide (1.18 g, 2.45 mmol) inanhydrous dichloromethane (20 mL) was stirred at room temperature for 4hours. The solution was washed successively with a saturated aqueoussolution of NaHCO₃ (150 mL), water (150 mL), a saturated aqueoussolution of NaCl (150 mL), dried over MgSO₄ and filtered. Removal of thesolvent under reduced pressure gave a solid which was purified by columnchromatography, using a Biotage 40S cartridge, eluting with 5% ethylacetate/95% hexane, to give7-bromo-1,4-diisopropyl-6-methyl-1,2,3,4-tetrahydroquinoxaline as awhite solid (480 mg, 70%).

¹H NMR (500 MHz; CDCl₃): δ1.16-1.15 (m, 12H), 2.25 (s, 3H), 3.16 (s,4H), 3.95 (quintet, J=6.6 Hz, 1H), 4.00 (quintet, J=6.6 Hz, 1H), 6.47(s, 1H), 6.73 (s, 1H).

d.3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzaldehyde

A mixture of7-bromo-1,4-diisopropyl-6-methyl-1,2,3,4-tetrahydroquinoxaline (469 mg,1.51 mmol), 2-methoxy-5-formylphenylboronic acid (407 mg, 2.26 mmol),potassium carbonate (834 mg, 6.03 mmol) and water (2.5 mL) in anhydrous1,2-dimethoxyethane (30 mL) was degassed with argon for 15 minutes priorto the addition of tetrakis(triphenylphosphine)palladium (0) (349 mg,0.30 mmol). The reaction mixture was heated under reflux for 8.5 hours,allowed to cool to room temperature and extracted with ethyl acetate(2×100 mL). The organic extracts were successively washed with water(100 mL), saturated aqueous NH₄Cl (100 mL), saturated aqueous NaCl (100mL), dried over MgSO₄ and filtered. Removal of the solvent under reducedpressure gave an oil which was purified by column chromatography, usinga Biotage 40S cartridge, eluting with 10% ethyl acetate/90% hexane. Thetitle compound was isolated as bright yellow solid (315 mg, 57%).

¹H NMR (500 MHz; CDCl₃): δ1.14 (d, J=6.6 Hz, 6H), 1.20 (d, J=6.8 Hz,6H), 2.01 (s, 3H), 3.19-3.17 (m, 2H), 3.27-3.25 (m, 2H), 3.86 (s, 3H),3.99 (quintet, J=6.6 Hz, 1H), 4.11 (quintet, J=6.6 Hz, 1H), 6.47 (s,1H), 6.51 (s, 1H), 7.03 (d, J=8.7 Hz, 1H), 7.72 (d, J=1.9 Hz, 1H), 7.84(dd, J=8.3 Hz, J=2.0 Hz, 1H), 9.90 (s, 1H).

Example 73-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzylidene-2,4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzylidene-2,4-thiazolidinedionemay be prepared in a similar manner as described in Example 1 using3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzaldehyde.

The intermediate3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzaldehydewas prepared as follows:

a. 3-Bromo-6-hydroxy-4-methoxy-benzaldehyde

A mixture of 2-hydroxy-4-methoxy-benzaldehyde (3.04 g, 20 mmol) andtetrabutylammonium tribromide (6.40 g, 20 mmol) in anhydrousdichloromethane (200 mL) was stirred at room temperature for 24 hours.The solution was washed successively with a saturated aqueous solutionof NaHCO₃ (150 mL), water (150 mL), a saturated aqueous solution of NaCl(150 mL), dried over MgSO₄ and filtered. Removal of the solvent underreduced pressure gave a solid which was purified by columnchromatography, using a Biotage 40M cartridge, eluting with 5% ethylacetate/95% hexane to give 3-bromo-6-hydroxy-4-methoxy-benzaldehyde as awhite solid (3.50 g, 76%).

¹H NMR (500 MHz; CDCl₃): δ3.94 (s, 3H), 6.47 (s, 1H), 7.67 (s, 1H), 9.68(s, 1H), 11.43 (s, 1H).

b.3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzaldehyde

A mixture of 3-bromo-6-hydroxy-4-methoxy-benzaldehyde (2 g, 8.66 mmol),(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid(3.18 g, 12.99 mmol), potassium carbonate (4.79 g, 34.63 mmol) and water(4 mL) in anhydrous 1,2-dimethoxyethane (140 mL) was degassed with argonfor 15 minutes prior to the addition oftetrakis(triphenylphosphine)palladium(0) (2.0 g, 1.73 mmol). Thereaction mixture was heated under reflux for 15 hours, allowed to coolto room temperature and extracted with ethyl acetate (2×100 mL). Theorganic extracts were successively washed with water (100 mL), asaturated aqueous solution of NH₄Cl (100 mL), a saturated aqueoussolution of NaCl (100 mL), dried over MgSO₄ and filtered. Removal of thesolvent under reduced pressure gave an oil which was purified by columnchromatography, using a Biotage 40M cartridge, eluting with 5% ethylacetate/95% hexane, to give3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzaldehydeas a white solid (2.2 g, 73%).

¹H NMR (500 MHz; CDCl₃): δ1.28 (s, 6H), 1.33 (s, 6H), 1.70 (s, 4H), 2.08(s, 3H), 3.84 (s, 3H), 6.51 (s, 1H), 7.07 (s, 1H), 7.15 (s, 1H), 7.31(s, 1H), 9.73 (s, 1H), 11.53 (s, 1H).

Example 83-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzylidene-2,4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzylidene-2,4-thiazolidinedionemay be prepared in a similar manner as described in Example 1 using3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzaldehyde.

The intermediate3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzaldehydewas prepared as follows:

To a solution of3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzaldehyde(1.04 g, 2.95 mmol) in acetone (20 mL) was added dimethylsulfate (0.37mL, 3.84 mmol) and potassium carbonate (490 mg, 3.55 mmol). The reactionmixture was stirred at room temperature for 15 hours and extracted withethyl acetate (2×50 mL). The organic extracts were successively washedwith water (100 mL) and a saturated aqueous solution of NaCl (100 mL),dried over MgSO₄ and filtered. Removal of the solvent under reducedpressure gave3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzaldehyde(1.05 g, 97%).

¹H NMR (500 MHz; CDCl₃): δ1.26 (s, 6H), 1.31 (s, 6H), 1.69 (s, 4H), 2.06(s, 3H), 3.87 (s, 3H), 3.99 (s, 3H), 6.50 (s, 1H), 7.05 (s, 1H), 7.13(s, 1H), 7.67 (s, 1H), 10.35 (s, 1H).

Example 93-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzylidene-2,4-thiazolidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzylidene-2,4-thiazolidinedionemay be prepared in a similar manner as described in Example 1 using3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthylen-2-yl)-2,4-dimethoxy-benzaldehyde.

The intermediate3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxy-benzaldehydewas prepared as follows:

a.6-(2,6-Dimethoxyphenyl)-1,1,4,4-tetramethy-1,2,3,4-tetrahydronaphthlene

A mixture of 2,6-dimethoxy-phenylboronic acid (1.0 g, 5.48 mmol),6-bromo-1,1,4,4 tetramethy 1,2,3,4-tetrahydronaphthalene (0.73 g, 2.74mmol) and potassium carbonate (1.50 g, 10.96 mmol) in1,2-dimethoxyethane (20 mL) and water (1.0 mL) was degassed with argonfor 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.60 g, 0.54mmol) was added and the mixture heated at reflux under argon for 5hours. The solution was cooled to room temperature, diluted with ethylacetate and washed successively with water and brine, dried overanhydrous magnesium sulfate, filtered and evaporated. The residue waschromatographed on silica gel (eluent: ethyl acetate/hexane, 1:9) togive 0.92 g of6-(2,6-Dimethoxyphenyl)-1,1,4,4-tetramethy-1,2,3,4-tetrahydronaphthlene.

b.6-(5-Bromo-2,6-dimethoxyphenyl)-1,1,4,4-tetramethy-1,2,3,4-tetrahydronaphthlene

To a solution of6-(2,6-dimethoxyphenyl)-1,1,4,4-tetramethy-1,2,3,4-tetrahydronaphthlene(340 mg, 1.05 mmol) in dichloromethane (10 mL) was added pyridiniumtribromide (335 mg, 1.05 mmol) and the reaction mixture stirred at roomtemperature overnight. The solution was diluted with ethyl acetate andwashed successively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated. The residue was purified on silica gel(eluent: ethyl acetate/hexane, 0.5:9.5) to give 0.24 g (57%) of6-(5-bromo-2,6-dimethoxyphenyl)-1,1,4,4-tetramethy-1,2,3,4-tetrahydronaphthlene.¹H NMR (500 MHz; CDCl₃): δ1.28 (s, 6H); 1.31 (s, 6H); 1.70 (s, 4H); 3.35(s, 3H); 3.73 (s, 3H); 7.14 (dd, J₁=1.5 Hz, J₂=8.5 Hz, 1H); 7.15 (dd,J₁=2.0 Hz, J₂=8.5 Hz, 1H); 7.30 (d, J=8.0 Hz, 1H); 7.36 (d, J=1.5 Hz,1H); 7.45 (d, J=8.0 Hz, 1H), 7.95 (br, 1H).

c.3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxy-benzaldehyde

To a solution of6-(5-bromo-2,6-dimethoxyphenyl)-1,1,4,4-tetramethy-1,2,3,4-tetrahydronaphthlene(0.24 g, 0.55 mmol) in anhydrous THF (6 mL) was added at −78° C. underargon n-BuLi (1.6 M in hexane, 0.7 mL, 1.1 mmol). The solution wasstirred for 5 minutes at −78° C. and N,N-dimethylformamide (0.13 mL,1.65 mmol) was added. The reaction mixture was stirred 2 hours at −78°C. then quenched with aqueous ammonium chloride and brought to roomtemperature. The solution was diluted with ethyl acetate and washedsuccessively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated. The residue was chromatographed andsilica gel (eluent: ethyl acetate/hexane, 1:9) to give 0.14 g (72%) of3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxy-benzaldehyde.¹H NMR (500 MHz; CDCl₃): δ1.29 (s, 6H); 1.32 (s, 6H); 1.72 (s, 4H); 3.37(s, 3H); 3.83 (s, 3H); 6.83 (d, J=9.0 Hz, 1H); 7.14 (dd, J₁=2.0 Hz,J₂=8.5 Hz, 1H); 7.33 (d, J=8.0 Hz, 1H); 7.36 (s, 1H); 7.85 (d, J=8.5 Hz,1H); 10.29 (s, 1H).

Example 103-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzylidene-2,4-thiazolidinedione

3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzylidene-2,4-thiazolidinedionemay be prepared in a similar manner as described in Example 1 using3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzaldehyde.

The intermediate3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzaldehydewas prepared as follows:

a. 1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-bromoquinoline

To a cooled solution of 7-methyl quinoline (5.00 g, 35 mmol) and nickel(II) chloride hexahydrate (1.40 g, 6 mmol) in methanol (130 mL) wasadded sodium borohydride (5.50 g, 140 mmol) portionwise. The reactionmixture was stirred at 0° C. for 1 hour and then at room temperature for3 hours. Hydrochloric acid (2N, 200 mL) was added to the black residueand the mixture stirred at room temperature until disappearance of theblack precipitate. The acidic solution was neutralized with concentratedammonium hydroxide and extracted with ether. The organic layer waswashed with brine and dried over anhydrous magnesium sulfate, filteredand evaporated to give 5.28 g of 7-methyl-1,2,3,4-tetrahydro-quinoline(100%), used without further purification. A mixture of7-methyl-1,2,3,4-tetrahydro-quinoline (1.20 g, 8.2 mmol), potassiumcarbonate (2.3 g, 16.4 mmol) and isopropyl iodide (3.3 mL, 32.8 mmol) inN,N-dimethylformamide (10 mL) was heated at 60° C. with stirring for 24hours. The solution was cooled to room temperature and washedsuccessively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated to give 1.28 g (82%) of1-isopropyl-7-methyl-1,2,3,4-tetrahydro-quinoline. To a solution of1-isopropyl-7-methyl-1,2,3,4-tetrahydro-quinoline (1.04 g, 5.5 mmol) indichloromethane was added tetrabutylammonium tribromide (2.65 g, 5.5mmol) and the solution stirred at room temperature for 5 hours. Thesolution was washed successively with water and brine, dried overanhydrous magnesium sulfate, filtered and evaporated. The residue waschromatographed and silica gel (ethyl acetate/hexane, 1:9) to give 1.00g of 6-bromo-1-isopropyl-7-methyl-1,2,3,4-tetrahydro-quinoline (67%).

¹H NMR (500 MHz; CDCl₃): δ1.10 (s, 3H); 1.11 (s, 3H); 1.81 (m, 2H); 2.20(s, 3H); 2.64 (m, 2H); 3.0.8 (m, 2H); 3.5 (m, 1H); 6.94 (s, 1H); 6.54(s, 1H); 7.08 (s, 1H).

b.3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzaldehyde

A mixture of 6-bromo-1-isopropyl-7-methyl-1,2,3,4-tetrahydro-quinoline(0.85 g, 3.16 mmol), 2-methoxy-5-formyl boronic acid (1.13 g, 6.31 mmol)and potassium carbonate (1.70 g, 12.64 mmol) in 1,2-dimethoxyethane (30mL) and water (1.5 mL) was degassed with argon for 15 minutes.Tetrakis(triphenylphosphine)palladium(0) (0.80 g, 0.63 mmol) was addedand the mixture heated at reflux under argon for 35 hours. The solutionwas cooled to room temperature, diluted with ethyl acetate and washedsuccessively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated. The residue was chromatographed andsilica gel (eluent: ethyl acetate/hexane, 1:9) to give 0.81 g of3-(1-isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzaldehyde(79%). ¹H NMR (500 MHz; CDCl₃): δ1.18 (s, 3H); 1.20 (s, 3H); 1.94 (m,2H); 2.06 (s, 3H); 2.72 (m, 2H); 3.18 (m, 2H); 3.85 (s, 3H); 4.16 (m,1H); 6.57 (s, 1H); 6.78 (s, 1H); 7.02 (d, 1H); 7.69 (d, 1H); 7.34 (s,1H); 7.84 (m, 1H); 9.89 (s, 1H).

Example 113-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzylidene-2,4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzylidene-2,4-thiazolidinedionemay be prepared in a similar manner as described in Example 1 using3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzaldehydeprepared from 3-bromo-4,5-dimethoxybenzaldehyde.

The intermediate 3-bromo-4,5-dimethoxybenzaldehyde was prepared asfollows:

To a solution of 5-bromovanillin (2.00 g, 8.65 mmol) in acetone (50 mL)was added potassium carbonate (1.4 g, 10.38 mmol) and dimethylsulfate (1mL, 10.38 mmol). The solution was stirred at room temperature for 16hours. The reaction mixture was diluted with ethyl acetate and theorganic layer was washed successively with water and brine, dried overanhydrous magnesium sulfate, filtered and evaporated to afford 1.88 g of3-bromo-4,5-dimethoxybenzaldehyde (89%).

Example 123-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzylidene)-2-thioxo-4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzylidene)-2-thioxo-4-thiazolidinedionewas prepared in a similar manner as described in Example 2 in a 57%yield using intermediate3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzaldehydedescribed in Example 4. ¹H NMR (500 MHz; CDCl₃) 1.25 (2 s, 6H); 1.32(2s, 6H); 1.69 (s, 4H); 2.05 (s, 3H); 3.84 (s, 3H); 6.88 (d, J=8.5 Hz,1H); 7.05 (s, 1H); 7.18 (s, 1H); 7.41 (t, J=8.5 Hz, 1H); 7.89 (s, 1H).

Example 133-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl]-2,4-thiazolidinedione,Also Referred to as Compound 13 Herein

To a solution of4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzylalcohol (195 mg, 0.57 mmol) in acetic acid (glacial, 3 mL) was added HBr(48%, 1 mL) and the resulting mixture heated at reflux for 2 hours. Thesolution was cooled to room temperature, diluted with ethyl acetate andwashed successively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated to afford 200 mg of crude4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzylbromide. To a stirred solution of 2,4-thiazolidinedione (133 mg, 1.14mmol) in anhydrous THF (6 mL) was added, at −78° C. under argon, n-BuLi(1.6M in hexane, 1.5 mL, 2.4 mmol) dropwise. The mixture was maintainedat −78° C. for 15 minutes and then warmed to 0° C. for 30 minutes tocomplete the dianion formation. Upon recooling to −78° C.,4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzylbromide was added in THF (3 mL). After 30 minutes the orange solutionwas allowed to warm to room temperature. After 1.5 hours, the solutionwas treated with 2N HCl, diluted with ethyl acetate and washedsuccessively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated. The residue was chromatographed onsilica gel (eluent: ethyl acetate/hexane 2:8) to give 61 mg of5-[4-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl]thiazolidine-2,4-dione(24% for 3 steps from benzaldehyde). ¹H NMR (500 MHz; CDCl₃): δ1.27 (s,6H); 1.26 (s, 6H); 1.69 (s, 4H); 2.08 (s, 3H); 3.12 (dd, J₁=14.0 Hz,J₂=9.5 Hz, 1H); 3.50 (dd, J₁=14.0 Hz, J₂=4.0 Hz, 1H); 3.76 (s, 3H); 4.54(dd, J₁=9.5 Hz, J₂=4.0 Hz, 1H); 6.89 (d, J=8.0 Hz, 1H); 7.03 (d, J=2 Hz,1H); 7.07 (s, 1H); 7.14 (s, 1H); 7.17 (dd, J₁=8.0 Hz, J₂=2.0 Hz, 1H),7.95 (br, 1H).

The intermediate4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzylalcohol was prepared as follows:

a.4-Methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzaldehyde

A mixture of 2-methoxy-5-formylphenylboronic acid (2.3 g, 12.80 mmol),6-bromo-1,1,4,4,7pentamethyl1,2,3,4-tetrahydronaphthalene (3.0 g, 10.66mmol) and potassium carbonate (5.89 g, 42.64 mmol) in1,2-dimethoxyethane (100 mL) and water (5 mL) was degassed with argonfor 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (2.4 g, 2.13mmol) was added and the mixture heated at reflux under argon for 8hours. The solution was cooled to room temperature, diluted with ethylacetate and washed successively with water and brine, dried overanhydrous magnesium sulfate, filtered and evaporated. The residue waschromatographed on silica gel (eluent: 0% to 25% ethyl acetate inhexane) to give 3.43 g (95%) of4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzaldehyde.¹H NMR (500 MHz; CDCl₃): δ1.26 (s, 6H); 1.32 (s, 6H); 1.70 (s, 4H); 2.08(s, 3H); 3.89 (s, 3H); 7.06 (d, J=8.5 Hz, 1H); 7.09 (s, 1H); 7.16 (s,1H); 7.71 (d, J=2.0 Hz, 1H); 7.88 (dd, J₁=8.5 Hz, J₂=2.0 Hz 1H), 9.91(s, 1H).

b.4-Methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzylalcohol

To a solution of4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzaldehyde(200 mg, 0.59 mmol) in methanol (5 mL) was added at 0° C. in smallportions sodium borohydride (70 mg, 1.77 mmol). The solution was stirred1 hour at 0° C. then quenched with 2N HCl. The reaction mixture wasdiluted with ethyl acetate and washed successively with water and brine,dried over anhydrous magnesium sulfate, filtered and evaporated toafford 195 mg (98%) of4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzylalcohol.

¹H NMR (500 MHz; CDCl₃): δ1.27 (s, 6H); 1.31 (s, 6H); 1.69 (s, 4H); 2.10(s, 3H); 3.78 (s, 3H); 4.65 (s, 2H); 6.94 (d, J=8.5 Hz, 1H); 7.10 (s,1H); 7.14 (s, 1H); 7.17 (d, J=2.0 Hz, 1H); 7.33 (dd, J₁=8.5 Hz, J₂=2.0Hz, 1H).

Example 145-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylidene-2-thioxo-4-thiazolidinedione

5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylidene-2-thioxo-4-thiazolidinedionemay be prepared in a similar manner as described in Example 2 usingintermediate2-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridine-5-carboxaldehydedescribed in Example 3.

Example 156-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylidene-2-thioxo-4-thiazolidinedione

6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylidene-2-thioxo-4-thiazolidinedionemay be prepared in a similar manner as described in Example 2 usingintermediate6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-5-methoxy-pyridine-2-carboxaldehydedescribed in Example 5.

Example 163-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzylidene-2-thioxo-4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzylidene-2-thioxo-4-thiazolidinedionemay be prepared in a similar manner as described in Example 2 usingintermediate3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzaldehydedescribed in Example 7.

Example 173-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzylidene-2-thioxo-4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzylidene-2-thioxo-4-thiazolidinedionemay be prepared in a similar manner as described in Example 2 usingintermediate3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzaldehydedescribed in Example 8.

Example 183-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzylidene-2-thioxo-4-thiazolidinedione

3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzylidene-2-thioxo-4-thiazolidinedionemay be prepared in a similar manner as described in Example 2 usingintermediate3-(1,4-diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzaldehydedescribed in Example 6.

Example 193-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzylidene-2-thioxo-4-thiazolidinedione

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzylidene-2-thioxo-4-thiazolidinedionemay be prepared in a similar manner as described in Example 2 usingintermediate3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthylen-2-yl)-2,4-dimethoxy-benzaldehydedescribed in Example 9.

Example 203-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzylidene-2-thioxo-4-thiazolidinedione

3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzylidene-2-thioxo-4-thiazolidinedionemay be prepared in a similar manner as described in Example 2 usingintermediate3-(1-isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzaldehydedescribed in Example 11.

Example 213-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzylidene-2-thioxo-4-thiazolidinedione

3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzylidene-2-thioxo-4-thiazolidinedionemay be prepared in a similar manner as described in Example 2 usingintermediate3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzaldehydewhich may be prepared from 3-bromo-4,5-dimethoxybenzaldehyde asdescribed in Example 13.

Example 223-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzyl)]-2,4-thiazolidinedione

3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzyl)]-2,4-thiazolidinedionemay be prepared as described in Example 13 using intermediate3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzaldehydeor alternatively by reducing the double bond of Example 4 {i.e.,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzylidene)-2,4-thiazolidinedione}by methods known in the art.

Example 235-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylmethylene]-2,4-thiazolidinedione

5-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylmethylene]-2,4-thiazolidinedionemay be prepared as described in Example 13 using intermediate2-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridine-5-carboxaldehydeor alternatively by reducing the double bond of Example 3 (i.e.,5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylidene-2,4-thiazolidinedione)by methods known in the art.

Example 246-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylmethylene]-2,4-thiazolidinedione

6-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylmethylene]-2,4-thiazolidinedionemay be prepared as described in Example 13 using intermediate6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-5-methoxy-pyridine-2-carboxaldehydeor alternatively by reducing the double bond of Example 5 (i.e.,6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylidene-2,4-thiazolidinedione)by methods known in the art.

Example 253-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl]-2-thioxo-4-thiazolidinedione

3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl]-2-thioxo-4-thiazolidinedionemay be prepared as described in Example 13 using intermediate3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzaldehydedescribed in Example 1 or alternatively by reducing the double bond ofExample 2 (i.e.,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2-thioxo-4-thiazolidinedione)by methods known in the art.

Example 263-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2-thioxo-4-imidazolidinedione

A mixture of 2-thioxo-4-imidazolidinedione (117 mg, 1.0 mmol),piperidine (0.07 mL, 0.7 mmol) and3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-methoxy-benzaldehyde(336 mg, 1.0 mmol) in ethanol (15 mL) was heated under reflux for 5hours, allowed to cool to room temperature, diluted with water andextracted with ethyl acetate (2×60 mL). The organic extracts were washedwith saturated aqueous NH₄Cl (60 mL), saturated aqueous NaCl (60 mL),dried over MgSO₄ and filtered. Removal of the solvent under reducedpressure gave a yellow solid that was purified by column chromatography,using a Biotage 40S cartridge, eluting with ethyl acetate/hexane (1:9).The title compound was isolated as a bright yellow solid (310 mg, 81%).

¹H NMR (500 MHz, DMSO-d₆): δ[1.22 (s) and 1.27(s), 12H], 1.65 (s, 4H),2.01 (s, 3H), 3.78 (s, 3H), 6.50 (s, 1H), 7.02 (s, 1H), 7.12 (d, J=8.7Hz, 1H), 7.17 (s, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.75 (dd, J₁=8.7 Hz,J₂=2.0 Hz, 1H), 12.19 (s, 1H), 12.27 (s, 1H).

³C NMR (125 MHz, DMSO-d₆): δ19.4, 31.7, 33.5, 33.6, 34.7, 55.5, 111.4,112.3, 124.7, 125.9, 127.2, 127.7, 131.0, 131.8, 132.4, 133.2, 135.0,141.3, 143.1, 157.5, 165.9, 178.6.

The intermediate4-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)benzaldehydewas prepared as described in Example 1.

Example 273-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzylidene-2,4-thiazolidinedione

Prepared in a similar manner to Example 1 in a 74% yield using4-hydroxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)benzaldehyde.

¹H NMR (500 MHz; DMSO-d₆) 1.22 (s, 6H), 1.27 (s, 6H), 1.64 (s, 4H), 2.07(s, 3H), 7.03 (s, 1H), 7.05 (d, J=8.7 Hz, 1H), 7.17 (s, 1H), 7.28 (d,J=2.0 Hz, 1H), 7.45 (dd, J₁=8.7 Hz, J₂=2.0 Hz, 1H), 7.74 (s, 1H), 10.32(s, 1H), 12.46 (s, 1H).

The intermediate4-hydroxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzaldehydewas prepared as follows:

To a solution of4-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)benzaldehyde(0.30 g, 0.89 mmol) in anhydrous dichloromethane (10 ml) at −78° C.under argon was added boron tribromide (0.17 mL, 1.78 mmol). Thesolution was slowly warmed to room temperature and stirred for 24 hrs.The solution was carefully poured onto ice water and extracted withethyl acetate. The organic layer was further washed with water andbrine, dried over anhydrous magnesium sulfate, filtered and evaporated.The residue was chromatographed on silica gel (Biotage, eluent: ethylacetate/hexane, 1:9) to give 0.24 g of product (84%). ¹H NMR (500 MHz;CDCl₃) 1.26 (s, 6H), 1.32 (s, 6H), 1.71 (s, 4H), 2.10 (s, 3H), 5.46 (s,1H), 7.11 (d, J=8.3 Hz, 1H), 7.13 (s, 1H); 7.26 (s, 1H); 7.69 (d, J=1.8Hz, 1H); 7.83 (dd, J₁=6.8 Hz, J₂=1.8 Hz, 1H), 9.89 (s, 1H).

Example 283-(3,5-Di-t-butyl-4-hydroxyphenyl)-3-methoxybenzylidene-2,4-thiazolidinedione

Prepared in a manner similar to Example 1 in a 50% yield using3-(3,5-di-t-butyl-4-hydroxyphenyl)-3-methoxybenzaldehyde.

¹H NMR (500 MHz, DMSO-d₆) 1.41 (s, 18H), 3.84 (s, 3H), 7.07 (s, 1H),7.24 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.53 (m, 2H), 7.83 (s, 1H), 12.5(s, 1H).

The intermediate3-(3,5-di-t-butyl-4-hydroxyphenyl)-3-methoxybenzaldehyde was prepared ina manner similar to the procedure described in Example 1b using4-bromo-2,6-di-t-butylphenol (0.50 g, 1.75 mmol),2-methoxy-5-formylphenyl boronic acid (0.315 g, 1.75 mmol),tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.175 mmol), K₂CO₃(0.95 g, 7.0 mmol), dimethoxyethane (15 mL) and H₂O (1 mL); 367 mg, 61%yield.

¹H NMR (500 MHz; CDCl₃) 1.48 (s, 18H), 3.93 (s, 3H), 5.30 (s, 1H), 7.08(d, J=8.0 Hz, 1H), 7.36 (s, 2H), 7.80-7.85 (m, 2H), 9.94 (s, 1H).

Example 293-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2,4-imidazolidinedione

A mixture of 2,4-imidazolidinedione (101 mg, 1.0 mmol), pyrrolidine(0.04 mL, 0.5 mmol) and3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-methoxy-benzaldehyde(336 mg, 1.0 mmol) in ethanol (15 mL) was heated under reflux for 24hours, allowed to cool to room temperature and extracted with ethylacetate (2×100 mL). The organic extracts were washed with saturatedaqueous NH₄Cl (60 mL), saturated NH₄Cl (70 mL), saturated aqueous NaCl(60 mL), dried over MgSO₄ and filtered. Removal of the solvent underreduced pressure gave a yellow solid that was purified by columnchromatography, using a Biotage 40S cartridge, eluting with ethylacetate/hexane (3:7). The title compound was isolated as a yellow solid(270 mg, 65%).

¹H NMR (500 MHz, DMSO-d₆): δ1.22 (s, 6H), 1.27 (s, 6H), 1.65 (s, 4H),2.00 (s, 3H), 3.75 (s, 3H), 6.42 (s, 1H), 7.01 (s, 1H), 7.08 (d, J=8.7Hz, 1H), 7.15 (s, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.62 (dd, J=2.6 Hz, J=8.8Hz, 1H), 10.52 (s, 1H), 11.13 (s, 1H).

¹³C NMR (125 MHz, DMSO-d₆): δ19.4, 31.7, 33.5, 33.6, 34.7, 55.4, 108.8,111.3, 125.3, 126.2, 127.1, 127.7, 130.4, 130.9, 131.8, 133.1, 135.2,141.2, 143.0, 155.7, 156.7, 165.6.

The intermediate4-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)benzaldehydewas prepared as described in Example 1.

Example 303-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-dimethylaminobenzylidene-2,4-thiazolidinedione

To a solution of toluene (30 mL) containing piperidine (0.2 mL) andacetic acid (0.2 mL) were added 2,4-thiazolidinedione (2.34 g, 20 mmol)and4-dimethylamino-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl)benzaldehyde(7.0 g, 20 mmol). The reaction mixture was heated at reflux for 4 hourswith continuous removal of water using a Dean-Stark water separator.After cooling to room temperature, a yellow solid formed that wascollected and washed with ethanol, dried under vacuum to give 5.7 g of5-[4-dimethylamino-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl)benzylidene]thiazolidine-2,4-dione.The organic layers were combined and evaporated. Trituration fromethanol afforded 1.4 g more of product (78%). ¹H NMR (300 MHz; d-DMSO):1.21 (s, 3H); 1.24 (s, 3H); 1.27 (s, 6H); 1.65 (s, 4H); 2.05 (s, 3H);2.55 (s, 6H); 7.06 (d, J=9 Hz, 1H); 7.13 (s, 1H); 7.20 (s, 1H); 7.21 (d,J=2.4 Hz, 1H); 7.46 (dd, J₁=2.1 Hz, J₂=8.7 Hz, 1H); 7.73 (s, 1H), 12.43(s, 1H).

The intermediate4-dimethylamino-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl)benzaldehydewas prepared as follows:

a. 3-Bromo-4-(dimethylamino)-benzaldehyde

To a solution of 4-(dimethylamino)-benzaldehyde (10.0 g, 67.03 mmol) indichloromethane (250 mL) was added pyridinium tribromide (21.4 g, 67.03mmol). The reaction mixture was stirred at room temperature overnight.The solution was washed successively with water and brine, dried overanhydrous magnesium sulfate, filtered and evaporated. Choromatography onsilica gel (15% EtOAc in hexane) afforded 14.06 g of3-bromo-4-(dimethylamino)-benzaldehyde (92%).

b.4-Dimethylamino-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzaldehyde

To a solution of 3-bromo-4-(dimethylamino)-benzaldehyde (5 g, 21.92mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl)boronicacid (6.5 g, 26.30 mmol) in a mixture of toluene (50 mL), ethanol (10mL) and water (7.5 mL) was added potassium carbonate (6.0 g, 43.83mmol). The solution was degased with argon for 30 minutes.Tetrakis(triphenylphosphine)palladium(0) (0.50 g, 0.438 mmol) was addedand the mixture heated at reflux under argon overnight. The solution wascooled to room temperature, diluted with ethyl acetate and washedsuccessively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated. The residue was chromatographed onsilica gel (8% ethyl acetate in hexane) to give 7.08 g of4-dimethylamino-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl)benzaldehyde(92%). ¹H NMR (300 MHz; DMSO) 1.22 (s, 3H); 1.28 (s, 3H); 1.29 (s, 3H);1.31 (s, 3H); 1.69 (s, 4H); 2.07 (s, 3H); 2.64 (s, 6H); 6.93 (d, J=8.4Hz, 1H); 7.13 (s, 1H); 7.15 (s, 1H); 7.58 (d, J=2.4 Hz, 1H); 7.75 (dd,J₁=8.7 Hz, J₂=2.1 Hz, 1H); 9.80 (s, 1H).

Example 313-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-chlorobenzylidene-2,4-thiazolidinedione

To a solution of toluene (30 mL) containing piperidine (0.26 mL, 2.64mmol) and acetic acid (0.26 mL) were added 2,4-thiazolidinedione (1.03g, 8.81 mmol) and4-chloro-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl)benzaldehyde(3.0 g, 8.81 mmol). The reaction mixture was heated at reflux for 12hours with continuous removal of water using a Dean-Stark waterseparator. After cooling to room temperature, a yellow solid formed thatwas collected and washed with ethanol, dried under vacuum to give 2.7 gof5-[4-chloro-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl)benzylidene]thiazolidine-2,4-dione(70% yield). ¹H NMR (300 MHz; DMSO-d₆): 1.19 (s, 3H); 1.20 (s, 3H); 1.25(s, 3H); 1.26 (s, 3H); 1.63 (s, 4H); 2.01 (s, 3H); 7.07 (s, 1H); 7.26(s, 1H); 7.52 (d, J=2.1 Hz, 1H); 7.59 (dd, J₁=2.1 Hz, J₂=8.1 Hz, 1H);7.71 (d, J=8.1 Hz, 1H); 7.83 (s, 1H); 12.68 (s, 1H).

The intermediate4-chloro-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl)benzaldehydewas prepared as follows:

a. Ethyl 3-bromo-4-chlorobenzoate

To a solution of 3-bromo-4-chlorobenzoic acid (3.00 g, 12.74 mmol) andcesium carbonate (6.23 g, 19.11 mmol) in acetonitrile (70 mL) was addediodoethane (5.1 mL, 63.7 mmol). The reaction mixture was heated atreflux overnight. After cooling to room temperature, the solution wasextracted with ethyl acetate. The organic layer was washed successivelywith water and brine, dried over anhydrous magnesium sulfate, filteredand evaporated. Choromatography on silica gel (biotage, 5% EtOAc inhexane) afforded 3.5 g of ethyl 3-bromo-4-chlorobenzoate (97%). ¹H NMR(300 MHz; CDCl₃) 1.40 (t, 3H); 4.37 (q, 2H); 7.52 (d, J=8.1 Hz, 1H);7.91 (dd, J₁=8.4 Hz, J₂=1.8 Hz, 1H); 8.28 (d, J=1.8 Hz, 1H).

b. 3-Bromo-4-chloro-benzyl alcohol

To a solution of ethyl-3-bromo-4-chlorobenzoate (3.25 g, 12.34 mmol) intoluene (70 mL) was added, at −78° C. under argon, diisobutylaluminumhydride (1.5M in toluene, 24 mL, 37.01 mmol). The reaction mixture wasstirred at −78° C. for 1 hr then methanol (9 mL) and water (18 mL) wasadded. The solution was warmed up to room temperature and extracted withethyl acetate. The organic layer was washed successively with water andbrine, dried over anhydrous magnesium sulfate, filtered and evaporatedto give 2.73 g of 3-bromo-4-chloro-benzyl alcohol.

c. 3-Bromo-4-chloro-benzaldehyde

To a solution of 3-bromo-4-chlorobenzyl alcohol (2.73 g, 12.34 mmol) indichloromethane (75 mL) was added, at room temperature, pyridiniumchlorochromate (2.66 g, 12.34 mmol). The reaction mixture was stirred atroom temperature for 1 hr then filtered over celite. The solvent wasremoved under reduced pressure and the residue chromatographed on silicagel (10% ethyl acetate in hexane) to afford 2.52 g of3-bromo-4-chloro-benzaldehyde (93% yield). ¹H NMR (300 MHz; CDCl₃) ¹HNMR (300 MHz; CDCl₃) 7.65 (d, J=8.1 Hz, 1H); 7.78 (dd, J₁=8.4 Hz, J₂=2.1Hz, 1H); 8.12 (d, J=2.1 Hz, 1H).

d.4-chloro-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl)benzaldehyde

To a solution of 3-bromo-4-chlorobenzaldehyde (2.5 g, 11.39 mmol),(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl)boronic acid(3.1 g, 12.53 mmol) in a mixture of toluene (25 mL), ethanol (5 mL) andwater (4 ML) was added potassium carbonate (3.15 g, 22.78 mmol). Thesolution was degased with argon for 30 minutes.Tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.23 mmol) was addedand the mixture heated at reflux under argon overnight. The solution wascooled to room temperature, diluted with ethyl acetate and washedsuccessively with water and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated. The residue was chromatographed onsilica gel (biotage: eluant:ethyl acetate/hexane, 5:95) to give 3.0 g of4-chloro-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl)benzaldehyde(77%). ¹H NMR (300 MHz; DMSO) 1.18 (s, 3H); 1.20 (s, 3H); 1.24 (s, 3H);1.26 (s, 3H); 1.36 (s, 4H); 1.98 (s, 3H); 7.04 (s, 1H); 7.23 (s, 1H);7.75 (d, J=7.8 Hz, 1H); 7.80 (d, J=1.8 Hz, 1H); 7.88 (dd, J₁=7.8 Hz,J₂=1.8 Hz, 1H); 9.99 (s, 1H).

Example 323-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione,also referred to as Compound 32 herein

To a solution of toluene (50 mL) containing piperidine (0.84 mL, 8.53mmol) and acetic acid (0.84 mL) was added 2,4-thiazolidinedione (3.3 g,28.43 mmol) and4-trifluoromethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzaldehyde(11.1 g, 28.43 mmol). The reaction mixture was heated at reflux withcontinuous removal of water using a Dean-Stark water separator. After 12hours at reflux 25 mL of toluene was removed by distillation and thesolution was cooled to room temperature. The yellow solid was collectedand taken up in ethanol (40 ml). After stirring at room temperature for15 minutes, the pale yellow solid was collected and washed with aminimum of ethanol, dried under vacuum to give 6.6 g of3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione.The organic layers were combined and evaporated. Further crystallizationfrom ethanol afforded an additional 2.0 g to give a total of 8.6 g (61%)of product. ¹H NMR (300 MHz; DMSO-d₆): 1.21 (s, 6H); 1.27 (s, 6H); 1.65(s, 4H); 2.04 (s, 3H); 7.08 (s, 1H); 7.26 (s, 1H); 7.62 (m, 2H); 7.70(dd, J₁=8.0 Hz, J₂=1.5 Hz, 1H); 7.86 (s, 1H); 12.5 (s, 1H).

The intermediate4-trifluoromethoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzaldehydewas prepared as follows:

a. 3-Bromo-4-trifluoromethoxybenzaldehyde

To a solution of 4-trifluoromethoxybenzaldehyde (215 g, 1.13 mol) in amixture of TFA (300 mL), CH₂Cl₂ (300 mL) and H₂SO₄ (150 mL) was added atroom temperature N-bromosuccinimide (402 g, 2.26 mol) in equal portionover 7 hours. The reaction mixture was stirred for 4 days at roomtemperature, poured into ice-water and extracted with CH₂Cl₂. Theorganic layer was washed with water then treated with saturated NaHCO₃(1.5 L) for 2 hrs. The layers were separated and the organic layerfurther washed with water and brine, dried over MgSO₄, filtered andevaporated. The residue was triturated with hexane and filtered. Afterevaporation of the solvent, the residue was distilled to give3-bromo-4-trifluoromethoxybenzaldehyde (190.2 g, 81° C., 1.0 mm/Hg,62%).

b.4-Trifluoromethoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzaldehyde.

To a solution of 3-bromo-4-trifluoromethoxybenzaldehyde (10.0 g, 37.2mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)boronicacid (11 g, 44.68 mmol, 1.2 eq) in a mixture of toluene (100 mL),ethanol (20 mL) and water (15 mL) was added potassium carbonate (10.28g, 74.4 mmol, 2 eq). The solution was degassed with argon for 40minutes. Tetrakis(triphenylphosphine)palladium(0) (0.86 g, 0.74 mmol,0.02 eq) was added and the mixture heated at reflux under argon for 22hours. The solution was cooled to room temperature, diluted with ethylacetate and washed successively with water and brine, dried over MgSO₄,filtered and evaporated. The residue was chromatographed on silica gel(silica: 70-230 mesh, 60A, 400 g, eluant: ethyl acetate/hexane, 5:95) togive4-trifluoromethoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzaldehyde(11.1 g, 76%). ¹H NMR (300 MHz; CDCl₃) 1.25 (s, 6H); 1.32 (s, 6H); 1.70(s, 4H); 2.08 (s, 3H); 7.06 (s, 1H); 7.18 (s, 1H), 7.48 (dd, J₁=8.4 Hz,J₂=1.5 Hz, 1H); 7.84 (d, J=2.0 Hz, 1H); 7.88 (dd, J₁=2.0 Hz), J₂=8.5 Hz1H), 9.91 (s, 1H).

Example 33 3T3-L1 Differentiation In Vitro Assay without Insulin

The following protocol was used to determine differentiation activity ofthe present invention. Differentiation of 3T3-L1 cells was assessed in96 well plates. Two-days after confluence, cells were treated witheither a test compound, such as Compound 1, or with a control, such asrosiglitazone. Drugs were replaced every 2-3 days for a total of 7 days.

Control for fully-differentiated adipocytes: Dexamethasone/Insulin (2.5μM; 10 μg/ml, respectively).

Working concentrations: 10⁻¹⁰ to 10⁻⁵M.

Cell line used: Mouse preadipocyte 3T3-L1, from passages #3-9 (3,000cells/well in 96-well plates). Culture media Growth medium (GM): DMEDulbecco's modified Eagle's medium containing 4500 mg/L glucose; 4 mML-glutamine; 10 U/ml Pen-G; 10 mcg/ml Streptomycin and 10% Bovine CalfSerum (CS).

Differentiation medium (DM): DME Dulbecco's modified Eagle's mediumcontaining 4500 mg/L glucose; 4 mM L-glutamine; 10 U/ml Pen-G; 10 mcg/mlStreptomycin and 10% Fetal Calf Serum (FCS).

Lysis procedure: Upon culmination of the treatment using a test compoundcells were washed once with PBS and lysed in situ with 50 μL 10%Hecameg. The lysates were further analyzed for their lipid content usingthe Triglyceride-GPO Trinder reagent from Sigma.

Example 34 3T3-L1 Differentiation In Vitro Assay with Insulin

The following protocol was used to determine differentiation activity ofthe present invention. Differentiation of 3T3-L1 cells was assessed in96 well plates. Two-days after confluence (day 0), cells were treatedwith either a test compound, such as Compound 1, or with a control, suchas rosiglitazone, in the presence of insulin (1.0 μg/mL). On day 2 noadditional insulin was added in the differentiation medium. Drugs werereplaced every 2-3 days for a total of 7 days.

Control for fully-differentiated adipocytes: Dexamethasone/Insulin (2.5μM; 10 μg/ml, respectively).

Working concentrations: 10⁻¹⁰ to 10⁻⁵ M.

Cell line used: Mouse preadipocyte 3T3-L1, from passages #3-9 (3,000cells/well in 96-well plates). Culture media Growth medium (GM): DMEDulbecco's modified Eagle's medium containing 4500 mg/L glucose; 4 mML-glutamine; 10 U/ml Pen-G; 10 mcg/ml Streptomycin and 10% Bovine CalfSerum (CS).

Differentiation medium (DM): DME Dulbecco's modified Eagle's mediumcontaining 4500 mg/L glucose; 4 mM L-glutamine; 10 U/ml Pen-G; 10 mcg/mlStreptomycin and 10% Fetal Calf Serum (FCS).

Lysis procedure: Upon culmination of the treatment using the testcompound cells were washed once with PBS and lysed in situ with 50 μL10% Hecameg. The lysates were further analyzed for their lipid contentusing the Triglyceride-GPO Trinder reagent from Sigma.

Example 35 Oral Administration of Compound 1 in the Early InterventionTreatment of Type 2 Diabetes in db/db Mutant Mice

Methods

Animals and Housing

Five week-old female db/db mutant mice (C57BL/KsJ-db +/+m; Jackson Labs)were housed in a fixed 12-12-hr artificial light-dark cycle, andmaintained on a standard high fat diet (containing at least 11% crudefat) provided ad libitum (Teklad S-2335). Animals were allowed two daysto acclimate in this experimental environment prior to the initiation ofthe study.

Dosage Groups and Treatment

Prior to initiation of treatment, the animals were bled from the tailvein (100-200 μL of whole blood) and serum levels of glucose andtriglycerides were measured in duplicate (Trinder kits; Sigma, St.Louis,Mo.). Based on these initial measures, animals (not yet hyperglycemic)were sorted into groups with approximately the same average serumglucose levels. Once sorted, the animals were housed six per cage andprovided high fat rodent diet ad libitum.

Experiment I: (Compound 1)

Treatment groups(n=6/group):

1) db/db control (sesame oil)

2) Compound 1 (0.3 mg/kg; twice daily)

3) Compound 1 (1 mg/kg; twice daily)

Experiment II: (Compound 32)

Treatment groups(n=6/group):

1) db/db control (sesame oil)

2) Compound 32 (0.3 mg/kg; once daily)

3) Compound 32 (1 mg/kg; once daily)

4) Compound 32 (3 mg/kg; once daily)

3) Rosiglitazone (1 mg/kg; only daily)

Drug is prepared by mixing Compound 1 or 32 in sesame oil, andadministered to animals in a volume of 5 ml/kg/dose. Drug isadministered by oral gavage daily at the beginning (Compound 1 and 32)and end of the artificial dark cycle (Compound 1; 12 hour interval).

Serum Measurements

To monitor the effect of Compound 1 or 32, animals were bled following athree-hour fast at the end of the dark cycle on days 12 of the treatmentperiod. Fasting serum glucose and triglyceride levels were measured induplicate. The blood is kept at room temperature to allow coagulation,after which the serum is separated and assayed for glucose andtriglyceride levels. As shown in FIGS. 2A, 2B, 4A and 4B, Compound 1 and32 prevented the onset of diabetes in both treatment groups with dosesas low as 0.3 mg/kg when administered once (Compound 32) or twice(Compound 1) a day. Both serum glucose and triglyceride levels remainedwell within the normal range compared to control animals, which showedthe typical hyperglycemia and hypertriglyceridemia associated with theonset of type 2 diabetes.

Example 36 Oral Administration of Compound 1 in the Late InterventionTreatment of Type 2 Diabetes in ob/ob Mutant Mice

Methods

Animals and Housing

Five week-old male ob/ob mutant mice (C57BL/6J-ob; Jackson Labs) werehoused in a fixed 12-12-hr artificial light-dark cycle, and maintainedon a standard diet provided ad libitum. Animals were allowed two days toacclimate in this experimental environment prior to the initiation ofthe study.

Dosage Groups and Treatment

Prior to initiation of treatment, the animals were bled from the tailvein (100-200 μL of whole blood) and serum levels of glucose andtriglycerides were measured in duplicate (Trinder kits; Sigma, St.Louis,Mo.). Based on these initial measures, hyperglycemic animals were sortedinto groups with approximately the same average serum glucose levels.Once sorted, the animals were housed six per cage and provided standardrodent diet ad libitum.

Treatment groups(n=6/group):

1) ob/ob control (sesame oil)

2) Compound 1 (5 mg/kg twice daily)

Drug is prepared by mixing Compound 1 in sesame oil, and administered toanimals in a volume of 3 ml/kg/dose. Drug is administered by oral gavagetwice daily at the beginning and end of the artificial dark cycle (12hour interval).

Serum Measurements

To monitor the effect of Compound 1, animals were bled following athree-hour fast at the end of the dark cycle on days 7 and 14 of thetreatment period. Fasting serum glucose and triglyceride levels weremeasured in duplicate. The blood is kept at room temperature to allowcoagulation, after which the serum is separated and assayed for glucoseand triglyceride levels. As shown in FIGS. 3A and 3B, Compound 1produced a significant decrease in serum glucose levels following 1 and2 weeks of treatment (p<0.05; ANOVA and Fisher's Least SignificantDifference; FIG. 3A). Similarly, treatment with Compound 1 for two weekssignificantly reduced triglyceride levels compared to control (p<0.05,FIG. 3B).

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

We claim:
 1. A compound of Formula (I):

wherein: m is 0 or 1; R₁ and R₂ together with the aromatic ring bondedthereto form a cycloalkyl, substituted cycloalkyl, cycloalkenyl orsubstituted cycloalkenyl residue that may optionally comprise 1 or 2heteroatoms selected from O, S, NH or N-alkyl; R₃ and R₄ areindependently or together hydrogen, alkyl, substituted alkyl, haloalkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen,cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino,di-substituted amino, alkylsulfonamide, arylsulfonamide, alkylurea,arylurea, alkylcarbamate, arylcarbamate, heteroaryl, alkoxy, substitutedalkoxy, haloalkoxy, thioalkyl, thiohaloalkyl, carboxy, carboalkoxy,alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide orsubstituted dialkylcarboxamide; Ar is Formula (II), (III), (IV) or (V):

where R₈, R₉ and R₁₀ are independently or together hydrogen, alkyl,substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino,mono-substituted amino, di-substituted amino, alkylamide,alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate,arylcarbamate, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl,thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide;R₅ is hydrogen, halogen, hydroxy, alkyl or substituted alkyl; -----represents a bond present or absent; and W, X, Y and together form a2,4-thiazolidinedione, or 2-thioxo-4-thiazolidinedione residue; or apharmaceutically acceptable salt thereof.
 2. A compound of claim 1wherein m is
 1. 3. A compound of claim 2 wherein R₁ and R₂ together withthe aromatic ring bonded thereto form a cycloalkyl or substitutedcycloalkyl optionally comprising 1 or 2 heteroatoms selected from O, NHand N-alkyl; and R₃ and R₄ are independently or together hydrogen,halogen, alkyl, substituted alkyl, haloalkyl, alkoxy, substitutedalkoxy, haloalkoxy, amino, mono-substituted amino or di-substitutedamino.
 4. A compound of claim 2 wherein Ar is Formula (VI), (VII) or(VIII):

wherein R₈ is alkyl, substituted alkyl, alkenyl, haloalkyl, hydroxy,acyloxy, halogen, alkoxy, substituted alkoxy, amino, mono-substitutedamino, di-substituted amino, alkylamide or haloalkoxy; and R₉ and R₁₀are independent or together hydrogen, halogen, alkyl, substituted alkyl,haloalkyl, alkenyl, substituted alkenyl, alkoxy, hydroxyl, amino,mono-substituted amino, di-substituted amino, alkylamide or haloalkoxy.5. A compound of claim 7 wherein ----- represents the bond is presentand the compound has the Formula (XV):


6. A compound of claim 1 wherein R₁ and R₂ together with the aromaticring bonded thereto form a substituted cycloalkyl; R₃ is methyl, ethyl,trifluoromethyl, methoxy or dimethylamino; and R₄ is hydrogen.
 7. Acompound of claim 1 wherein R₁, R₂, R₃, and R₄ together with thearomatic ring bonded thereto form a residue selected from:3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl,3-ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl,3-trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl,3-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl, or3-dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl. 8.The compound of claim 1 present as:3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzylidene)-2,4-thiazolidinedione,5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylidene-2,4-thiazolidinedione,6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylidene-2,4-thiazolidinedione,or3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2-thioxo-4-thiazolidinedione;or a pharmaceutically acceptable salt thereof.
 9. The compound of claim1 present as:3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzylidene-2,4-thiazolidinedione,3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzylidene-2,4-thiazolidinedione,3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzylidene-2,4-thiazolidinedione,3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2,4-thiazolidinedione,3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzylidene-2,4-thiazolidinedione,or3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzylidene-2,4-thiazolidinedione;or a pharmaceutically acceptable salt thereof.
 10. The compound of claim1 present as:3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzylidene-2-thioxo-4-thiazolidinedione,5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylidene-2-thioxo-4-thiazolidinedione,6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylidene-2-thioxo-4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzylidene-2-thioxo-4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzylidene-2-thioxo-4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzylidene-2-thioxo-4-thiazolidinedione,3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzylidene-2-thioxo-4-thiazolidinedione,3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzylidene-2-thioxo-4-thiazolidinedione,3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2-thioxo-4-thiazolidinedione,3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzylidene-2-thioxo-4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzylidene-2-thioxo-4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzylidene-2-thioxo-4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzylidene-2-thioxo-4-thiazolidinedione,or3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzylidene-2-thioxo-4-thiazolidinedione;or a pharmaceutically acceptable salt thereof.
 11. A compound of claim 1present as3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione;or a pharmaceutically acceptable salt thereof.
 12. A compound of claim 2present as3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-dimethylaminobenzylidene-2,4-thiazolidinedione;or a pharmaceutically acceptable salt thereof.
 13. A compound of claim 1present as:3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-chlorobenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methylbenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-ethylbenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethylbenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-ethoxybenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-ethoxy-2-fluorobenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-isopropoxybenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methylamino-5-bromobenzylidene-2,4-thiazolidinedione;or3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-aminobenzylidene-2,4-thiazolidinedione;or a pharmaceutically acceptable salt thereof.
 14. A compound of claim 1present as:3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-acetamidobenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-ethoxy-2,5-difluorobenzylidene-2,4-thiazolidinedione,3-(3-Methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione,3-(3-Dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione,3-(3-Trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzylidene-2,4-thiazolidinedione,3-(3-Trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methylbenzylidene-2,4-thiazolidinedione,3-(3-Trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-ethylbenzylidene-2,4-thiazolidinedione,3-(3-Trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione,3-(3-Dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-dimethylaminobenzylidene-2,4-thiazolidinedione,3-(3-Trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-chlorobenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-acetoxybenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-hydroxybenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-(1-propen-3-yl)-benzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxy-5-fluorobenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxy-2,5-difluorobenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,6-difluorobenzylidene-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5,6-difluorobenzylidene-2,4-thiazolidinedione,3-(3-Trifluoromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-dimethylaminobenzylidene-2,4-thiazolidinedioneor3-(3-Ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedione;or a pharmaceutically acceptable salt thereof.
 15. A compound of claim 4wherein ----- represents the bond is absent and the compound has theFormula (XVI):


16. The compound of claim 2 present as:3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl]-2,4-thiazolidinedione,3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzyl]-2,4-thiazolidinedione,3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-dimethylaminobenzyl]-2,4-thiazolidinedione,3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzyl)]-2,4-thiazolidinedione,5-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylmethylene]-2,4-thiazolidinedione,6-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylmethylene]-2,4-thiazolidinedioneor3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl]-2-thioxo-4-thiazolidinedione;or a pharmaceutically acceptable salt thereof.
 17. The compound of claim1 present as:3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl]-2,4-thiazolidinedione,3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzyl]-2,4-thiazolidinedione,3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-dimethylaminobenzyl]-2,4-thiazolidinedione,3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-fluoro-4-methoxybenzyl)]-2,4-thiazolidinedione,5-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-6-methoxy-3-pyridylmethylene]-2,4-thiazolidinedione,6-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-5-methoxy-2-pyridylmethylene]-2,4-thiazolidinedioneor3-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl]-2-thioxo-4-thiazolidinedione;or a pharmaceutically acceptable salt thereof.
 18. The compound of claim1 present as:3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzyl-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dimethoxybenzyl-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,6-dihydroxybenzyl-2,4-thiazolidinedione,3-(1,4-Diisopropyl-6-methyl-1,2,3,4-tetrahydro-7-quinoxalinyl)-4-methoxybenzyl-2,4-thiazolidinedione,3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxybenzyl-2,4-thiazolidinedione,3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxybenzyl-2,4-thiazolidinedione,3-(1-Isopropyl-7-methyl-1,2,3,4-tetrahydro-6-quinolinyl)-4-methoxybenzyl-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4,5-dimethoxybenzyl-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-hydroxybenzyl-2,4-thiazolidinedione,3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-5-fluorobenzyl-2,4-thiazolidinedione,or3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-2,5-difluorobenzyl-2,4-thiazolidinedione;or a pharmaceutically acceptable salt thereof.
 19. A compound of claim 1wherein R₁ and R₂ together with the aromatic ring bonded thereto form acycloalkyl or substituted cycloalkyl optionally comprising 1 or 2nitrogen heteroatoms; and R₃ is alkyl or substituted alkyl.
 20. Aprocess for the preparation of a compound of the Formula (XV)

wherein: R₁ and R₂ together with the aromatic ring form a cycloalkyl,substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyloptionally comprising 1 or 2 heteroatoms selected from O, S, NH andN-alkyl; R₃ and R₄ are independently or together hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino,mono-substituted amino, di-substituted amino, alkylsulfonamide,arylsulfonamide, alkylurea, arylurea, alkylcarbamate, arylcarbamate,heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl,thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide;Ar is Formula (II), (III), (IV) or (V):

where R₈, R₉ and R₁₀ are independently or together hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino,mono-substituted amino, di-substituted amino, alkylamide,alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate,arylcarbamate, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl,thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide;R₁₁ is hydrogen, alkyl or substituted alkyl; R₅ is hydrogen, halogen,hydroxy, alkyl or substituted alkyl; ----- represents a bond present orabsent; and W, X, Y and Z together form a 2,4-thiazolidinedione, or2-thioxo-4-thiazolidinedione residue; comprising the steps of: 1)coupling a first aryl residue with a second aryl residue to give abiaryl carbonyl containing compound; wherein the first aryl residue hasthe structure:

and wherein the second aryl residue has a carbonyl group and has thestructure:

and wherein the biaryl carbonyl containing compound has the structure:

 and 2) condensing the biaryl carbonyl containing compound with anactive methylene compound of the structure:

to give the benzylidene compound of Formula (XV).
 21. A process of claim20 further comprising the step of reducing the benzylidene to form thebenzyl compound of Formula (XVI):


22. A compound having the formula3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-trifluoromethoxybenzylidene-2,4-thiazolidinedioneor a pharmaceutically acceptable salt thereof.
 23. A compound having theformula3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-dimethylaminobenzylidene-2,4-thiazolidinedioneor a pharmaceutically acceptable salt thereof.